Novel pyridazine derivatives and medicines containing the same as effective ingredients

ABSTRACT

This invention relates to pyridazine derivatives represented by the formula (1):  
                 
 
wherein R 1  represents a (substituted) aryl group, R 2  represents a phenyl group substituted at  4 -position by a lower alkoxyl group or a lower alkylthio group, R 3  represents a lower alkoxyl group, a halogenated lower alkyl group, a lower cycloalkyl group, a (subsituted) aryl group, a (substituted) aryloxy group, a (substituted) nitrogen-containing heterocyclic ring residue, a (substituted) aminocarbonyl group or a lower alkylcarbonyl group, A represents a single bond, a lower alkylene group or a lower alkenylene group, X represents O or S, and the dashed line indicates that the carbon-carbon bond between the  4 -position and the  5 -position is a single bond or a double bond, or salts thereof; and also to medicines containing them as effective ingredients. These compounds have excellent inhibitory activity against interleukin- 1 β production, and are useful as preventives and therapeutics for immmune system diseases, inflammatory diseases, ischemic diseases and the like.

TECHNICAL FIELD

This invention relates to novel pyridazine derivatives, which haveexcellent inhibitory activity -against interleukin-1β production and areuseful for the prevention and treatment of immune system diseases,inflammatory diseases, ischemic diseases and the like, and also tomedicines containing them as effective ingredients.

BACKGROUND ART

In many diseases, for example, rheumatism, arthritis, osteoporosis,inflammatory colitis, immune deficiency syndrome, ichorrhemia,hepatitis, nephritis, ischemic diseases, insulin-dependent diabetesmellitus, arterial sclerosis, Parkinson's disease, Alzheimer's disease,leukemia and the like, stimulation of interleukin-1β production, aninflammatory cytokine, is observed. This interleukin-1β serves to inducesynthesis of an enzyme which is considered to take part in inflammationlike collagenase and PLA2 and, when intra-articularly injected toanimals, causes multi-articular destruction highly resembling rheumatoidarthritis. On the other hand, interleukin-1 is controlled in activity byinterleukin-1 receptor, soluble interleukin-1 receptor and interleukin-1receptor antagonist.

From research conducted making use of recombinants of thesebioactivity-inhibiting substances, anti-interleukin-1β antibodies andanti-receptor antibodies against various disease models, interleukin-1βhas been found to play an important role in the body, leading to anincreasing potential of substances having interleukin-1β inhibitoryactivity as therapeutics for such diseases.

For example, immunosuppressors and steroids which are used for thetreatment of rheumatism out of such many diseases have been reported toinhibit the production of interleukin-1β. Even among medicamentscurrently under development, KE298, a benzoylpropionic acid derivative[The Japanese Society of Inflammation (11th), 1990], for example, hasbeen reported to have inhibitory activity against interleukin-1βproduction although it is an immunoregulator. Inhibitory activityagainst interleukin-1β production is also observed on a group ofcompounds which are called “COX-2 selective inhibitors”, for example,nimesulide as a phenoxysulfonanilide derivative (DE 2333643), T-614 as aphenoxy-benzopyran derivative (U.S. Pat. No. 4,954,518), and tenidap(hydroxyindole derivative) as a dual inhibitor (COX-1/5-LO).

For all of these compounds, however, interleukin-1 production inhibitoryactivity is not their primary action so that their inhibitory activityagainst interleukin-1° production is lower than their primary action.

In recent years, increasingly active research is under way for thesynthesis of compounds with a focus placed on inhibitory activityagainst interleukin-1β production. Production inhibitors synthesized insuch research can be classified into a group of compounds which inhibitthe transfer process of an inflammatory signal to a cell nucleus andanother group of compounds which inhibit an enzyme ICE that functions inthe processing of a precursor of interleukin-1β. Known examples ofcompounds presumed to have the former action include SB203580 [JapaneseLanguage Laid-Open (Kokai) Publication (PCT) No. HEI 7-503017], FR167653(Eur. J. Pharm., 327, 169-175, 1997), E-5090 (EP 376288), CGP47969A(Gastroenterology, 109, 812-828, 1995), hydroxyindole derivatives (Eur.J. Med. Chem. 31, 187-198, 1996), and triarylpyrrole derivatives (WO97/05878), while known examples of compounds presumed to have the latteraction include VE-13,045 which is a peptide compound (Cytokine, 8(5),377-386, 1996).

None of these compounds can however exhibit sufficient inhibitoryactivity against interleukin-1β production.

On the other hand, a variety of 5,6-diphenyl-pyridazine derivatives areknown to have analgesic and anti-inflammatory action (EUR. J. MED.CHEM., 14, 53-60, 1979). Absolutely nothing has however been known withrespect to inhibitory activity against interleukin-1β production bythese 5,6-diphenyl-pyridazine derivatives.

Accordingly, an object of the present invention is to provide a compoundhaving excellent inhibitory activity against interleukin-1β productionand also a medicine containing it as an effective ingredient.

DISCLOSURE OF THE INVENTION

Under such circumstances, the present inventors have proceeded with anextensive investigation. As a result, it has been found that pyridazinederivatives represented by the below-described formula (1) haveexcellent inhibitory activity against interleukin-1β production and areuseful as medicines for the prevention and treatment of immune systemdiseases, inflammatory diseases, ischemic diseases and the like, leadingto the completion of the present invention.

Namely, the present invention provides a pyridazine derivativerepresented by the following formula (1):

wherein R¹ represents a substituted or unsubstituted aryl group, R² is aphenyl group substituted at least at 4-position by a lower alkoxylgroup, a lower alkyl-thio group, a lower alkylsulfinyl group or a loweralkylsulfonyl group, and optionally has one or more substituents at theremaining positions, R³ represents a hydrogen atom, a lower alkoxylgroup, a halogenated lower alkyl group, a lower cycloalkyl group, asubstituted or unsubstituted aryl group, a substituted or. unsubstitutedaryloxy group, a substituted or unsubstituted, nitrogen-containingheterocyclic ring residue, a substituted or unsubstituted aminocarbonylgroup, or a lower alkylcarbonyl group, A represents a single bond or alinear or branched lower alkylene group or lower alkenylene group, Xrepresents an oxygen atom or a sulfur atom, and the dashed lineindicates that the carbon-carbon bond between the 4-position and the5-position is a single bond or a double bond, with the proviso that A isa single bond when R³ is a halogenated lower alkyl group and that thefollowing combinations are excluded: R¹ and R² are 4-methoxy-phenylgroups, X is an oxygen atom, the carbon-carbon bond at the 4-positionand the 5-position is a double bond, A is a single bond, and R³ is ahydrogen atom or a 2-chloroethyl group; or a salt thereof.

Further, the present invention also provides a medicine comprising thepyridazine derivative (1) or the salt thereof as an effectiveingredient.

Furthermore, the present invention also provides a pharmaceuticalcomposition comprising the pyridazine derivative (1) or the salt thereofand a pharmaceutically acceptable carrier.

Moverover, the present invention also provides use of the pyridazinederivative (1) or the salt thereof as a medicine.

In addition, the present invention also provides a method for treating adisease caused by stimulation of interleukin-1β production, whichcomprises administering the pyridazine derivative (1) or the saltthereof.

As will be demonstrated in tests to be described subsequently herein,the inhibitory activity against interleukin-1β production by thepyridazine derivative (1) or the salt thereof is extremely strong andreaches 100 to 1,000 times as high as the action of the above-describedknown 5,6-diphenylpyridazine derivatives (EUR. J. MED. CHEM. 14, 53-60,1979).

BEST MODE FOR CARRYING OUT THE INVENTION

The pyridazine derivative according to the present invention isrepresented by the formula (1). In the formula, illustrative of the arylgroup represented by R¹ can be phenyl, naphthyl and pyridyl, with phenyland pyridyl being particularly preferred. These aryl groups may contain1 to 3 substituents. Examples of such substituents can include halogenatoms, lower alkyl groups, lower alkoxyl groups, lower alkylthio groups,lower alkylsulfinyl groups, lower alkylsulfonyl groups, carboxyl group,lower alkoxycarbonyl groups, nitro group, amino group, and loweralkylamino groups. Here, illustrative of the halogen atoms can befluorine, chlorine, bromine and iodine. The lower alkyl groups are thosecontaining 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl,isopropyl and n-butyl. Illustrative of the lower alkoxyl groups can bethose containing 1 to 6 carbon atoms, for example, methoxy, ethoxy andpropoxy. Illustrative of the lower alkylthio groups can be thosecontaining 1 to 6 carbon atoms, for example, methylthio, ethylthio andpropylthio. Illustrative of the lower alkylsulfinyl groups can be thosecontaining 1 to 6 carbon atoms, for example, methylsulfinyl,ethylsulfinyl and propylsulfinyl. Illustrative of the loweralkylsulfonyl groups can be those containing 1 to 6 carbon atoms, forexample, methylsulfonyl, ethylsulfonyl and propylsulfonyl. Illustrativeof the lower alkoxycarbonyl groups can be those having alkoxyl groupseach of which contains 1 to 6 carbon atoms, for example,methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl. Illustrative of thelower alkylamino groups can be those having one or two alkyl groups eachof which contains 1 to 6 carbon atoms, for example, methylamino,dimethylamino, ethylamino and propylamino. The lower alkyl moieties inthese substituents may be linear, branched or cyclic.

Preferred as R¹ is a phenyl or pyridyl group, which may be substitutedby 1 to 3 substituents selected from halogen atoms and lower alkoxylgroups, these substituents being preferably present at 3-, 4- or5-position.

Preferred as R² is a phenyl group, which may be substituted at4-position by a lower alkoxyl group, a lower alkylthio group, a loweralkylsulfinyl group or a lower alkylsulfonyl group, and at the otherposition by 1 or 2 substituents selected from halogen atoms, loweralkoxyl groups, lower alkylthio groups, lower alkylsulfinyl groups andlower alkylsulfonyl groups. Examples of the halogen atom, lower alkoxylgroup, lower alkylthio group, lower alkylsulfinyl group and loweralkylsulfonyl group as the substituents on the phenyl group as R²include the same groups as those recited as R¹. These substituents arepreferably positioned at only 4-position, at 3- or 4-position, or at anyof 3-, 4- or 5-position.

Illustrative of the lower alkoxyl group and the substituted orunsubstituted aryl group out of those represented by R³ can be similarto those exemplified above in connection with R¹.

Illustrative of the halogenated lower alkyl group can be lower alkylgroups substituted by one or more halogen atoms as exemplified above inconnection with R¹.

Examples of the lower cycloalkyl group can include those having 3 to 8carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

Illustrative of the aryloxy group can be a phenyloxy group, which maycontain similar substituent or substituents as in the case of R¹.

Illustrative of the nitrogen-containing heterocyclic ring residue can besaturated, nitrogen-containing heterocyclic ring residue such aspiperidino, piperidyl, piperazino and morpholino; andnitrogen-containing aromatic heterocyclic ring residue such as pyridyl.These residue may contain similar substituents as in the case of R¹.Further, each of them may additionally contain one or more carbonylgroups bonded thereto.

The aminocarbonyl group may contain similar substituents as in the caseof R¹ and also aralkyl groups such as benzyl and phenethyl.

Illustrative of the lower alkylcarbonyl group can be those containing 1to 6 carbon atoms, for example, methylcarbonyl and ethylcarbonyl.

Preferred examples of R³ can include a hydrogen atom; lower alkoxylgroups; halogenated lower alkyl groups; lower cycloalkyl groups; phenyl,pyridyl and phenyloxy groups each of which may be substituted by 1 to 3substituents selected from halogen atoms, lower alkyl groups, loweralkoxyl groups, carboxyl group, lower alkoxycarbonyl groups, nitrogroup, amino group, lower alkylamino groups and lower alkylthio groups;substituted or unsubstituted piperidino, piperidyl, piperazino andmorpholino groups; and substituted or unsubstituted aminocarbonylgroups; and lower alkylcarbonyl groups.

Among those represented by A, the lower alkylene group can be a linearor branched one having 1 to 6 carbon atoms, examples of which caninclude methylene, ethylene and trimethylene. The lower alkenylene groupcan be a linear or branched one having 2 to 9 carbon atoms, with onehaving 2 to 6 carbon atoms and 1 to 3 double bonds being preferred.Illustrative can be ethenylene, propenylene, butenylene andbutadienylene.

Preferred examples of A can be linear or branched lower alkylene groupshaving 1 to 6 carbon atoms and linear or branched, lower alkenylenegroups having 2 to 9 carbon atoms.

Preferred examples of the pyridazine derivative (1) can include thosecontaining, as R¹, a phenyl or pyridyl group substituted by 1 to 3substituents selected from halogen atoms and lower alkoxy groups; as R²,a phenyl group, which may be substituted at 4-position by a loweralkoxyl group, a lower alkylthio group, a lower alkylsulfinyl group or alower alkylsulfonyl group, and at the other position by 1 or 2substituents selected from halogen atoms, lower alkoxyl groups, loweralkylthio groups, lower alkylsulfinyl groups and lower alkylsulfonylgroups; as R³, a hydrogen atom, a lower alkoxyl group, a halogenatedlower alkyl group, a lower cycloalkyl group, or a phenyl, pyridyl orphenyloxy group which may be substituted by 1 to 3 substituents selectedfrom halogen atoms, lower alkyl groups, lower alkoxyl groups, carboxylgroup, lower alkoxycarbonyl groups, nitro group, amino group, loweralkylamino groups and lower alkylthio groups, a substituted orunsubstituted piperidino, piperidyl, piperazino or morpholino group, asubstituted or unsubstituted aminocarbonyl group, or a loweralkylcarbonyl group; and as A, a linear or branched lower alkylene grouphaving 1 to 6 carbon atoms or a linear or branched lower alkenylenegroup having 2 to 9 carbon atoms.

In the present invention, compounds represented by the following formula(1A) are also preferred:

wherein R⁴ represents a linear or branched lower alkyl or lower alkenylgroup, a lower cycloalkyl group or a lower cycloalkylmethyl group, and Xrepresents an oxygen atom or a sulfur atom.

In the formula (1A), examples of the lower alkyl group out of thoserepresented by R⁴ can include linear or branched lower alkyl groupshaving 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl and n-hexyl. Examples of the loweralkenyl group can include linear or branched lower alkenyl groups having2 to 6 carbon atoms, preferably 2 to 4 carbon atoms and 1 to 2 doublebonds, for example, ethenyl, propenyl, butenyl, isobutenyl andbutadienyl. Examples of the lower cycloalkyl group can include thosehaving 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl,cyclo-pentyl and cyclohexyl. Illustrative of the lower cycloalkyl groupin the lower cycloalkyl methyl group can be those exemplified above.

Particularly preferred examples of R⁴ can include alkyl groups having 1to 4 carbon atoms, alkenyl groups having 2 to 4 carbon atoms, cycloalkylgroups having 3 to 6 carbon atoms, and cycloalkylmethyl groups.

Preferred examples of the pyridazine derivative (1) can include5,6-bis(4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-isopropyl-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one,2-allyl-5,6-bis(4-methoxy-phenyl)-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-cyclopropyl-2H-pyridazin-3-one,5,6-bis(4-methoxy-phenyl)-2-cyclopropylmethyl-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazine-3-thione,5,6-bis(4-methoxyphenyl)-2-cyclopentyl-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-cyclo-pentylmethyl-2H-pyridazin-3-one,5,6-bis(4-methoxy-phenyl)-2-(4-chlorocinnamyl)-2H-pyridazin-3-one,5-(4-chlorophenyl)-6-(4-methylthiophenyl)-2-benzyl-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-benzyl-2H-pyridazine-3-thione, and5,6-bis(3-fluoro-4-methoxy-phenyl)-2-ethyl-2H-pyridazin-3-one.

No particular limitation is imposed on the salt of the pyridazine (1),said salt also pertaining to the present invention, insofar as it is apharmacologically acceptable salt. Illustrative can be acid additionsalts of mineral acids, such as the hydrochloride, hydrobromide,hydroiodide, sulfate, nitrate and phosphate; and acid addition salts oforganic acids, such as the benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate,tartrate and citrate.

Further, the compounds according to the present invention may exist inthe form of solvates represented by hydrates and also in the form ofketo-enol tautomers. Such solvates and isomers should also beencompassed by the present invention.

The pyridazine derivatives (1) according to the present invention can beprepared, for example, by the following processes.

wherein R⁵ represents a lower alkyl group, and R¹, R² ₁ R³ and A havethe same meanings as defined above.

A description will be made specifically about respective preparationprocesses of compounds (1a), (1b), (1c), (1d) and (1e) among thepyridazine derivatives (1).

(1) Preparation of 4,5-dihydro-2H-pyridazin-3-one derivatives (1a: inthe formula (1), A is a single bond, R³ is a hydrogen atom, X is anoxygen atom, and a single bond is formed between the 4-position and the5-position):

A 4,5-dihydro-2H-pyridazin-3-one derivative (1a) can be obtained byreacting a haloacetate ester with a 2-arylacetophenone derivative (2)and then reacting hydrazine hydrate with the resultant product.

The 2-arylacetophenone derivative (2) as the starting material can beprepared, for example, by a known process (YAKUGAKU ZASSHI, 74, 495-497,1954).

The reaction between the compound (2) and the haloacetate ester can beconducted in the presence of a base in a solvent. Potassiumtert-butoxide, lithium diisopropylamide (LDA) or the like can bementioned as a base usable here, and tetrahydrofuran or the like can bementioned as a solvent usable here. The reaction is brought tocompletion at −20 to 40° C. in 1 to 10 hours, preferably at −5 to 25° C.in 2 to 5 hours.

Further, the reaction between the resultant compound (3) and hydrazinehydrate can be conducted in a solvent, and anhydrous hydrazine may beused in place of hydrazine hydrate. As the solvent, a lower alcohol suchas ethanol, methanol, n-propanol or isopropanol, tetrahydrofuran,1,4-dioxane or the like can be used. The reaction is brought tocompletion at 50 to 150° C. in 5 to 50 hours, preferably at 80 to 100°C. in 10 to 30 hours.

(2) Preparation of 4,5-dihydro-2H-pyridazin-3-one derivatives (1d: inthe formula (1), a single bond is formed between the 4-position and the5-position, and X is an oxygen atom.):

A 2-substituted 4,5-dihydro-2H-pyridazin-3-one derivative (1d) can beobtained by reacting a compound, which is represented by the formula:R³-A-NHNH₂.2HClwherein R³ and A have the same meanings as defined above, with thecompound (3) in the presence of sodium acetate in a solvent.

As a solvent usable in this reaction, methanol, ethanol, n-propanol,isopropanol, dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran,1,4-dioxane or the like can be mentioned. A lower alcohol or awater-containing lower alcohol is particularly preferred. The reactionis brought to completion at 40 to 150° C. in 1 to 80 hours, preferablyat 50 to 120° C. in 5 to 50 hours.

(3) Preparation of 2H-pyridazin-3-one derivatives (1b: in the formula(1), A is a single bond, R³ is a hydrogen atom, X is an oxygen atom, anda double bond is formed between the 4-position and the 5-position):

(i) Preparation by a dehydrogenating reaction:

A 2H-pyridazin-3-one derivative (1b) can be obtained by reacting adehydrogenating agent with the compound (1a) in acetic acid.

As the dehydrogenating agent, bromine,2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). or the like can beused. As the solvent, acetic acid or the like is usable. The reaction isbrought to completion at 30 to 150° C. in 5 to 50 hours, preferably at50 to 120° C. in 10 to 30 hours.

(ii) Preparation by a dehydrating reaction:

A 2H-pyridazin-3-one derivative (1b) can be obtained by reactingglyoxalic acid—which has been formed by causing sodium periodate to acton tartaric acid under acidic conditions—with the 2-aryl-acetophenonederivative (2) under basic conditions, reacting hydrazine hydrate withthe resultant 2-hydroxy-4-oxobutanoic acid derivative (4) in a loweralcohol as a solvent to convert it into a4,5-dihydro-4-hydroxy-2H-pyridazin-3-one derivative (5), and thensubjecting the derivative (5) to a dehydrating reaction in a solventwhile using para-toluenesulfonic acid hydrate as a catalyst.

In the reaction between the compound (2) and glyoxalic acid,commercially-available glyoxalic acid hydrate can also be used in placeof glyoxalic acid formed by causing sodium periodate to act on tartaricacid. As an acid usable upon formation of glyoxalic acid, an inorganicacid such as sulfuric acid, hydro-chloric acid or phosphoric acid can bementioned. As a base usable in the reaction between the compound (2) andglyoxalic acid, an inorganic base such as caustic soda or caustic potashor an organic base such as benzyltrimethylammonium hydroxide (Triton B)can be mentioned. In these reactions, the synthesis step of glyoxalicacid is brought to completion generally at −15 to 30° C. in 20 to 180minutes, preferably around 0 to 25° C. in 30 to 60 minutes. The reactionwith the compound (2) is conducted preferably at 0 to 120° C., and isbrought to completion by reacting them, preferably at room temperaturefor 10 to 25 hours and then at 70° C. for 0.5 to 2 hours. As thesolvent, a lower alcohol such as ethanol, methanol, n-propanol oriso-propanol, tetrahydrofuran, 1,4-dioxane or the like can be used.Concerning the reaction between the compound (4) and hydrazine hydrate,anhydrous hydrazine can also be used in place of hydrazine hydrate. Thereaction is brought to completion at 50 to 150° C. in 5 to 30 hours,preferably at 80 to 100° C. in 10 to 20 hours. As the solvent, a loweralcohol such as ethanol, methanol, n-propanol or isopropanol,tetrahydrofuran, 1,4-dioxane or the like can be used. In the dehydratingreaction of the compound (5), para-toluenesulfonic acid hydrate or thelike can be used as a catalyst. As the solvent, toluene, benzene or thelike can be used. The reaction is brought to completion at 50 to 150° C.in 3 to 50 hours, preferably at 80 to 130° C. in 5 to 30 hours.

(4) Preparation of 2H-pyridazin-3-one derivatives (1c: in the formula(1), X is an oxygen atom, and a double bond is formed between the4-position and the 5-position.):

-   -   (i) Preparation of the compound (1c) from the compound (1b):        -   (a) Preparation by a reaction between (1b) and a halide or            reactive ester:

2-Substituted 2H-pyridazin-3-one derivatives of a certain type (1c) caneach be obtained by reacting a compound, which is represented by thefollowing formula:R³-A-Ywherein R³ and A have the same meanings as defined above and Yrepresents a halogen atom or an OH group already converted into areactive ester group, with the compound (1b) in the presence of a basein a solvent.

As a base usable in this reaction, an inorganic base such as potassiumcarbonate or sodium carbonate or an organic base such as a metalalkoxide can be mentioned. As the solvent, N,N-dimethylformamide,dimethyl sulfoxide, acetone, methyl ethyl ketone or the like can beused. The reaction is brought to completion at 20 to 150° C. in 1 to 20hours, preferably at 50 to 130° C. in 2 to 10 hours.

Each compound (1c) in which the 2-substituent is a piperidylalkyl groupcan be prepared by protecting the nitrogen atom of the piperidyl alkanolas the starting material, converting the hydroxyl group into a reactiveester group, reacting the compound (1b) with the resultant compound, andthen conducting deprotection. Further, its N-lower alkylation makes itpossible to prepare an N-(lower alkyl)piperidylalkyl derivative.

As a protecting group for the nitrogen atom of the piperidyl alkanol, atert-butoxycarbonyl group, a benzyloxycarbonyl group, adimethylphosphinothioyl group or the like is preferred. The compoundprotected by such a group can be obtained by reacting di-tert-butylcarbonate, benzyloxycarbonyl chloride or the like with the piperidylalkanol in the presence of a base such as triethylamine or4-dimethylaminopyridiene. As a solvent, tetrahydrofuran, diethyl ether,ethyl acetate, methylene chloride, chloroform, N,N-dimethyl-formamide,dimethyl sulfoxide, ethanol, iso-propanol or the like can be used. Thereaction is brought to completion at −15 to 50° C. in 5 to 50 hours,preferably at 0 to 20° C. in 1 to 30 hours.

As the reactive ester group of the hydroxyl group, a tosyloxy group, amesyloxy group, a benzene-sulfonyloxy group or the like is preferred. Acompound which contains such a group can be obtained by reactingpara-toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonicanhydride, benzenesulfonyl chloride or the like with the N-protectedpiperidyl alkanol in the presence of a base such as pyridine,triethylamine or collidine. As a solvent, pyridine, tetrahydrofuran,diethyl ether, ethyl acetate, methylene chloride, chloroform,N,N-dimethylformamide, dimethyl sulfoxide or the like can be used. Thereaction is brought to completion at −15 to 50° C. in 1 to 50 hours,preferably at −5 to 30° C. in 1 to 10 hours.

The reaction between the compound (1b) and the reactive ester derivativeof the N-protected piperidyl alkanol can be conducted in the presence ofa base in a solvent. As a base usable here, an inorganic base such aspotassium carbonate or sodium carbonate or an organic base such as ametal alkoxide can be mentioned. As a solvent, N,N-dimethylformamide,dimethyl sulfoxide, acetone, methyl ethyl ketone or the like can beused. The reaction is brought to completion at 20 to 150° C. in 1 to 30hours, preferably at 50 to 130° C. in 2 to 10 hours.

The deprotection of the protecting group on the nitrogen atom of thepiperidyl group can be effected by heating the N-protected piperidylalkanol in the presence of an acid catalyst in a solvent. As an acidusable here, hydrochloric acid, sulfuric acid, acetic acid or the likecan be mentioned. Such an acid may be in a form diluted with water.Preferred is 2 to 10 N hydrochloric acid, with 4 to 8 N hydrochloricacid being particularly preferred. As the solvent, tetra-hydrofuran,methanol, ethanol, isopropanol, N,N-dimethylformamide or the like can beused. The reaction is brought to completion at 40 to 150° C. in 0.5 to10 hours, preferably at 50 to 130° C. in 2 to 5 hours.

The N-lower alkylation of the thus-deprotected piperidylalkyl derivativecan be conducted by reacting a lower alkyl sulfate, a lower alkyl halideor the like in the presence of a base in a solvent. As a base usablehere, sodium hydrogencarbonate, potassium carbonate or the like can bementioned. As the solvent, acetone, dimethyl sulfoxide,N,N-dimethylformamide, tetrahydrofuran, a mixed solvent thereof or thelike is preferred. The reaction is brought to completion at 20 to 150°C. in 0.5 to 10 hours, preferably at 50 to 130° C. in 1 to 5 hours.

(b) Preparation via a 2-hydroxyalkyl derivative:

A compound (1c) the 2-substituent of which is a piperidinoalkyl,piperazinoalkyl or morpholinoalkyl group can be prepared by convertingthe hydroxyl group of the 2-hydroxyalkyl derivative, which has beenobtained by reacting an alkylene chlorohydrin or alkylene carbonate withthe compound (1b), into a reactive ester group and then reacting acorresponding amine.

The synthesis of the 2-hydroxyalkyl derivative can be conducted byreacting the compound (1b) with an alkylene chlorohydrin in the presenceof a base, for example, in a known manner [Eur. J. Med. Chem.-Chim.Ther., 14(1), 53-60, 1979] or by heating the compound (1b) and thealkylene carbonate in the presence or absence of a quaternary ammoniumsalt as a catalyst in a solvent. As a quaternary ammonium salt usablehere, tetraethylammonium iodide, tetraethylammonium bromide,tetra(n-butyl)ammonium iodide, tetra(n-butyl)ammonium bromide or thelike can be mentioned. As the solvent, N,N-dimethylformamide, dimethylsulfoxide, N-methyl-pyrrolidone or the like can be mentioned. Thereaction is brought to completion at 80 to 180° C. in 0.5 to 10 hours,preferably at 120 to 160° C. in 1 to 5 hours.

As the reactive ester group of the hydroxyl group, a tosyloxy group, amesyloxy group, a benzene-sulfonyloxy group or the like is preferred. Acompound having such a group can be obtained by reactingparatoluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonicanhydride, benzenesulfonyl chloride or the like with the hydroxylalkylderivative in the presence of a base such as pyridine, triethylamine orcollidine. As a solvent, pyridine, terahydrofuran, diethyl ether, ethylacetate, methylene chloride, chloroform, N,N-dimethylformamide,dimethylsulfoxide or the like can be used. The reaction is brought tocompletion at −15 to 50° C. in 1 to 50 hours, preferably at −5 to 30° C.in 1 to 10 hours.

The reaction between the reactive ester derivative and the amine can beconducted by heating the reactive ester derivative in the presence of anexcess amount of the amine in a solvent or in a solventless manner orreacting the amine in the presence of an organic amine such as pyridine,triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or the like oran inorganic base such as potassium carbonate or sodium carbonate. Asthe solvent, dimethyl sulfoxide, pyridine, chloroform, methylenechloride, toluene, benzene or the like can be used besidesN,N-dimethylformamide. The reaction is brought to completion at 0 to150° C. in 1 to 10 hours, preferably at 50 to 130° C. in 1 to 5 hours.

(c) Preparation via a 2-carboxyalkyl derivative:

A compound (1c) the 2-substituent of which is an aminocarbonylalkylgroup can be prepared by reacting a haloalkyl carboxylate with thecompound (1b), hydrolyzing the ester group of the resultant 2-alkylcarboxylate ester derivative, converting it into a reactive acylderivative, and then reacting it with a corresponding amine orcondensing the carboxylic acid derivative and a corresponding amine witha condensing agent such as 1,3-dicyclohexylcarbodiimide (DCC).

As a base usable in the reaction between the compound (1b) and thehaloalkyl carboxylate, an inorganic base such as potassium carbonate orsodium carbonate or an organic base such as Triton B can be mentioned.As a solvent, N,N-dimethylformamide, dimethyl sulfoxide, acetone, methylethyl ketone or the like can be used. The reaction is brought tocompletion at 20 to 150° C. in 1 to 30 hours, preferably at 50 to 120°C. in 2 to 20 hours.

The hydrolyzing reaction of the ester group can be conducted by treatingthe ester derivative in the presence of a base such as caustic soda orcaustic potash in a conventional manner.

As the reactive derivative of the carboxylic acid, an acid halide, amixed acid anhydride or the like can be mentioned. The acid halide canbe prepared with oxalyl chloride, thionyl chloride, thionyl bromide orthe like, while the mixed acid anhydride can be synthesized with aceticanhydride, pivalic anhydride, methanesulfonic anhydride,para-toluenesulfonyl chloride or the like.

The reaction between these reactive ester derivative and amine can beconducted by reacting the reactive ester derivative with an excessamount of the amine in a solvent or in a solventless manner or byreacting the amine in the presence of an organic amine such as pyridine,triethylamine or DBU or an inorganic base such as potassium carbonate orsodium carbonate. As the solvent, tetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, pyridine, chloroform,methylene chloride, toluene, benzene or the like can be used. Thereaction is brought to completion at 0 to 150° C. in 1 to 10 hours,preferably at 50 to 130° C. in 1 to 5 hours.

(d) Preparation by other processes:

Among 2-substituted derivatives (1c), each derivative in which R³ is anaminophenyl group can be obtained by reducing the nitro group of acompound in which R³ is a nitrophenyl group, and its N-lower alkylationmakes it possible to prepare an N-(lower alkyl)aminophenyl compound.

The reduction of the nitro group can be effected by conductinghydrogenation in an inert solvent such as ethyl acetate or ethanol whileusing palladium on charcoal or Raney nickel as a catalyst.

The thus-reduced product can be N-lower alkylated by reacting it with alower alkyl sulfate, a lower alkyl halide or the like in the presence ofa base in a solvent. The resulting N-monoalkyl and dialkyl derivativescan be isolated, respectively, from their mixture.

As the base employed in the N-lower alkylating reaction, sodiumhydrogencarbonate, potassium carbonate, pyridine, triethylamine or thelike can be mentioned. As the solvent, acetone, dimethyl sulfoxide,N,N-dimethylformamide or tetrahydrofuran, a mixed solvent of two or moreof these solvents, or the like is preferred. The reaction is brought tocompletion at 20 to 150° C. in 0.5 to 10 hours, preferably at 50 to 130°C. in 1 to 5 hours.

(ii) Preparation of the compound (1c) from the compound (1d):

Using the compound (1d) as a starting material, the compound (1c) can beprepared in a similar manner as in the preparation of the compound (1b)from the compound (1a).

(iii) Preparation of compounds (1c) in each of which R¹ or R² is a loweralkylsulfinylphenyl group:

Among the compounds (1c), each derivative in which R¹ or R² is a loweralkylsulfinylphenyl group can be prepared by selectively oxidizing aderivative (1c) in which R¹ or R² is a lower alkylthiophenyl group.

The selective oxidizing reaction can be conducted usingmetha-chloroperbenzoic acid, hydrogen peroxide solution or the like asan oxidizing agent. The reaction is brought to completion at −30 to 30°C. in 10 minutes to 10 hours, preferably at −10 to 10° C. in 30 minutesto 1 hour. As a solvent, methylene chloride, chloroform or the like canbe used.

(iv) Preparation of compounds (1c) in each of which R¹ or R² is a loweralkylsulfonylphenyl group:

Among the compounds (1c), each derivative in which R¹ or R² is a loweralkylsulfonylphenyl group can be prepared by oxidizing a derivative (1c)in which R¹ or R² is a lower alkylthiophenyl group.

The oxidizing reaction can be conducted using osmium tetraoxide-sodiumperiodate, metha-chloroperbenzoic acid or the like as an oxidizingagent. The reaction is brought to completion at −30 to 50° C. in 1 to 24hours, preferably at 0 to 20° C. in 5 to 10 hours. As a solvent,acetone-water-chloroform or the like can be used.

(5) Preparation of 2H-pyridazin-3-thione derivatives (1e: in the formula(1), X is a sulfur atom, and a double bond is formed between the4-position and the 5-position.):

Each 2H-pyridazine-3-thione derivative (1e) can be obtained bythioketonizing its corresponding 2H-pyridazin-3-one derivative withLawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) ina solvent.

It is preferred to use Lawesson's reagent in 0.5 to 3 equivalents,notably 1 to 1.5 equivalents relative to the 2H-pyridazin-3-onederivative. The reaction is brought to completion at 30 to 150° C. in 1to 10 hours, preferably at 50 to 100° C. in 2 to 8 hours. As a usablesolvent, toluene, xylene or the like can be mentioned.

The intermediates and target compounds obtained in the above-describedindividual reactions can be separated and purified by purificationmethods commonly employed in organic synthesis chemistry, for example,by subjecting them to filtration, extraction, washing, drying,concentration, recrystallization, various chromatographic treatment, andthe like. The intermediates may be provided for the next reactionswithout purifying them specifically. Further, they may also be obtainedas solvates of solvents such as reaction solvents or recrystallizationsolvents, especially as hydrates.

The pyridazine derivatives (1) and their salts according to the presentinvention, which are available as described above, have excellentinhibitory activity against interleukin-1β production, and are usefulfor the prevention and treatment of diseases caused by stimulation ofinterleukin-1β production, for example, immune system diseases,inflammatory diseases, ischemic diseases, osteoporosis, ichorrhemia andthe like, especially as medicines such as preventives and therapeuticsfor rheumatism, immune deficiency syndrome, arthritis, inflammatorycolitis, ischemic heart diseases, ischemic encephalopathy, ischemicnephritis, ischemic hepatitis, insulin-dependent diabetes mellitus,arterial sclerosis, Parkinson's disease, Alzheimer's disease, leukemiaand the like or as interleukin-1β production inhibitors.

Medicines according to the present invention contain the pyridazinederivatives (1) or their salts as effective ingredients. Theiradministration routes can include, for example, oral administration bytablets, capsules, granules, powders, syrups or the like and parenteraladministration by intravenous injections, intramuscular injections,suppositories, inhalants, transdermal preparations, eye drops, nasaldrops or the like. Upon formulation of pharmaceutical compositions ofthese various unit dosage forms, pharmaceutically acceptable carrierscan be mixed with these effective ingredients. As such carriers,excipients, binders, extenders, disintegrators, surfactants, lubricants,dispersants, buffers, preservatives, corrigents, perfumes, coatingagents, vehicles, diluents and the like can be used by combining them asdesired.

The dosage of each medicine according to the present invention variesdepending on the age, body weight, conditions, administration form,administration frequency and the like. In general, however, it ispreferred to orally or parenterally administer to an adult the effectiveingredient in an amount of about 0.01 to 1,000 mg, preferably 0.1 to 100mg per day at once or in several portions.

EXAMPLES

The present invention will next be described in further detail by thefollowing Examples. It should however be borne in mind that the presentinvention is not limited to these Examples.

Preparation Example 1 (1) Preparation of3,4-bis(4-methoxyphenyl)-2-hydroxy-4-oxobutanoic acid

To a solution of sodium periodate (11.1 g, 52.0 mmol) in water (65 ml),concentrated sulfuric acid (1.12 ml) was added dropwise little by littleunder ice-water cooling and stirring. Subsequent to the dropwiseaddition, the temperature of the resulting mixture was allowed to riseto room temperature, followed by the addition of a solution of tartaricacid (7.81 g, 52.0 mmol) in water (18 ml). The mixture was stirred for50 minutes. To the reaction mixture, an aqueous solution of sodiumhydroxide and a suspension of 2-(4-methoxyphenyl)-4′-methoxyacetophenone(13.32 g, 52.0 mmol) in ethanol (160 ml) were added. The mixture wasstirred at 40° C. for 5 hours and then at room temperature for 17 hours,and a reaction was then conducted at 70° C. for 1 hour. Subsequent tocooling, the ethanol was distilled off. The liquid residue was washedwith ethyl acetate, acidified with hydrochloric acid, and then extractedwith ethyl acetate. The organic layer was washed with a saturatedaqueous solution of sodium chloride (brine) and then dried overanhydrous sodium sulfate. The solvent was distilled off, whereby thetitle compound (16.11 g, 93.8%) was obtained as a brown oil.

(2) Preparation of5,6-bis(4-methoxyphenyl)-4,5-dihydro-4-hydroxy-2H-pyridazin-3-one

Hydrazine hydrate (2.4 ml, 49.4 mmol) was added to a solution of3,4-bis(4-methoxyphenyl)-2-hydroxy-4-oxobutanoic acid (16.11 g, 48.8mmol) in ethanol. (240 ml), followed by heating under reflux for 15hours at a bath temperature of 100° C. The ethanol was distilled off,whereby the title compound (15.82 g, 99.4%) was obtained as a crudebrown oil.

¹H-NMR (CDCl₃) δ: 3.75(3H,s), 3.78(3H,s), 4.02(1H,brs), 4.25(1H,d),4.44(1H,d,J=3.91 Hz), 6.81(2H,d,J=9.04 Hz), 6.82(2H,d,J=8.79 Hz),7.10(2H,d,J=8.54 Hz), 7.58(2H,d,J=9.04 Hz), 9.03(1H,s).

(3) Preparation of 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one

To a solution of5,6-bis(4-methoxyphenyl)-4,5-dihydro-4-hydroxy-2H-pyridazin-3-one (15.82g, 48.5 mmol) in benzene (300 ml), para-toluenesulfonic acid monohydrate(1.82 g, 9.6 mmol) was added. A Dean-Stark apparatus was fitted,followed by heating under reflux for 5 hours. Para-toluenesulfonic acidmonohydrate (0.50 g) was added, followed by heating under reflux for 18hours. The benzene was distilled off, and the residue was extracted withethyl acetate (500 ml). After the organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate, it was washedwith a brine and then dried over anhydrous sodium sulfate. The waterlayers were combined and then extracted with chloroform (200 ml×3). Theorganic layer was washed with a brine and then dried over anhydroussodium sulfate. From the ethyl acetate extract and the chloroformextract, the solvents were distilled off. The residue was separated andpurified by chromatography on a silica gel column [silica gel: 50 g,chloroform/methanol (50/1)]. An eluate was concentrated to dryness underreduced pressure, and resulting crystals were heated in ethanol. Afterthe ethanol solution was cool, diethyl ether was added and thethus-obtained solution was left over at room temperature. A precipitatewas collected by filtration and then dried at 60° C. under reducedpressure, whereby the title compound (7.84 g, 52.4%) was obtained aspale orange crystals.

Colorless prisms (ethyl acetate-hexane)

Melting point: 240.5-242.5° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.81(3H,s), 6.78(2H,d,J=9.03 Hz),6.82(2H,d,J=9.03 Hz), 6.93(1H,s), 7.06(2H,d,J=9.03 Hz), 7.13(2H,d,J=9.04Hz), 11.42(1H,s).

IR (KBr) cm⁻¹: 1665,1607,1510,1301,1256,1027,838.

Preparation Example 2 Preparation of methyl4-(4-methoxyphenyl)-4-oxo-3-(4-pyridyl)butanoate

Under an argon, 2-(4-pyridyl)-4′-methoxyaceto-phenone (J. Am. Chem.Soc., 112, 2163-3168, 1990: Dimitrios Stefanidis and John W. Bunting;9.6 g, 42.3 mmol) was suspended in tetrahydrofuran (200 ml), and underice cooling, lithium diisopropylamide (2.0 M solution; 25 ml, 50.0 mmol)was added. At the same temperature, the mixture was stirred for 30minutes. Methyl bromoacetate (6.0 ml, 63.4 mmol) was then addeddropwise, and the mixture was stirred under ice cooling for 1 hour andthen at room temperature for 2. hours. The reaction mixture was dilutedwith toluene. The mixture was washed successively with 2 N hydrochloricacid, water and a brine, and was then dried over anhydrous sodiumsulfate. The solvent was distilled off and the residue was separated andpurified by chromatography on a silica gel column [silica gel: 100 g,hexane/ethyl acetate (1/2)], whereby the title compound (10.63 g, 84.1%)was obtained as a brown oil. ¹H-NMR (CDCl₃) δ: 2.71(1H,dd,J=5.37,16.84Hz), 3.35(1H,dd,J=9.28,16.84 Hz), 3.65(3H,s), 3.85(3H,s),5.04(1H,dd,J=5.37,9.28 Hz), 6.88(2H,d,J=9.03 Hz), 7.23(2H,d,J=6.10 Hz)7.93(2H,d,J=9.03 Hz), 8.52(2H,d,J=6.10 Hz).

IR (film) cm⁻¹: 1763,1674,1600,1512,1418,1263,1170.

Preparation Example 3 (1) Preparation of2-(4-chlorophenyl)-4′-(methyl-thio)acetophenone

A mixture consisting of para-chlorophenyl acetic acid (17.06 g, 0.1mol), thioanisole (24.84 g, 0.2 mol) and polyphosphoric acid (67.59 g,0.2 mmol) was heated at 100° C. for 7 hours. Water was added to thesolidified reaction product, and a white solid insoluble in water wascollected by filtration and then washed with n-hexane. The solid wasrecrystallized from a mixed solvent of ethanol and ethyl acetate,whereby the title compound (21.24 g, 76.7%) was obtained. Further, themother liquor was separated and purified by chromatography on a silicagel column (ethyl acetate). Recrystallization was then conducted fromethyl acetate, whereby the title compound (2.86 g, 10.4%) was obtained.

Colorless prisms (ethyl acetate)

Melting point: 161.1-162.1° C.

¹H-NMR (CDCl₃) δ: 2.51(3H,s), 4.21(2H,s), 7.19(2H,d,J=8.55 Hz),7.26(2H,d,J=8.91 Hz), 7.29(2H,d,J=8.55 Hz), 7.89(2H,d,J=8.91 Hz).

(2) Preparation of ethyl3-(4-chlorophenyl)-4-[4-(methylthio)phenyl]-4-oxobutanoate

A suspension of 2-(4-chlorophenyl)-4′-(methyl-thio)acetophenone (34.98g, 126.4 mmol) in tetrahydrofuran (350 ml) was ice-cooled, followed bythe addition of potassium tert-butoxide (17.01 g, 151.6 mmol) under anitrogen gas atmosphere. At the same temperature, the mixture wasstirred for 10 minutes. After ethyl bromoacetate (25.33 g, 151.7 mmol)was added dropwise over 10 minutes, the mixture was stirred at the sametemperature for 30 minutes. The reaction mixture was poured into toluene(350 ml), to which ice water (350 ml) was added, followed by extraction.The organic layer was collected. Further, the water layer was extractedwith toluene (100 ml). The thus-obtained organic layers were combined,washed with a brine (300 ml), and then dried over anhydrous sodiumsulfate. The solvent was distilled off, whereby the title compound(45.54 g, quantitative) was obtained as a yellow oil.

¹H-NMR (CDCl₃) δ: 1.19(3H,t,J=7.1 Hz), 2.47(3H,s), 2.70(1H,dd,J=5.4,16.9Hz), 3.31(1H,dd,J=9.4,16.9 Hz), 4.09(2H,q,J=7.1 Hz),5.01(1H,dd,J=5.4,9.4 Hz), 7.16-7.28(6H,m), 7.86(2H,d,J=8.7 Hz).

IR (film) cm⁻¹: 1738,1733,1683,1590,1252,1233,1178, 1094,820.

Preparation Example 4 Preparation of methyl3-(4-chlorophenyl)-4-[4-(methylthio)phenyl]-4-oxobutanoate

Using 2-(4-chlorophenyl)-4′-(methylthio)-acetophenone as a startingmaterial, the procedures of Preparation Example 2 were repeatedlikewise, whereby the title compound was obtained as a pale yellow oilin a yield of 95.8%.

¹H-NMR (CDCl₃) δ: 2.56(3H,s), 2.61(1H,dd,J=5.37,16.97 Hz),3.24(1H,dd,J=9.28,16.97 Hz), 3.55(3H,s), 4.94(1H,dd,J=5.37,9.28 Hz),7.10(2H,d,J=8.55 Hz), 7.12-7.20(4H,m), 7.77(2H,d, J=8.84 Hz).

IR (film) cm⁻¹: 1736,1675,1590,1490,1437,1403,1252, 1234,1173,1094.

Preparation Example 5 Preparation of methyl3-(4-fluorophenyl)-4-[4-(methylthio)phenyl]-4-oxobutanoate

Using 2-(4-fluorophenyl)-4′-(methylthio)-acetophenone as a startingmaterial, the procedures of Preparation Example 2 were repeatedlikewise, whereby the title compound was obtained as a pale yellow oilin a yield of 86.5%.

¹H-NMR (CDCl₃) δ: 2.45(3H,s), 2.70(1H,dd,J=5.31,16.91 Hz),3.32(1H,dd,J=9.40,16.91 Hz), 3.63(3H,s), 5.04(1H,dd,J=5.11,9.40 Hz),6.96(2H,t,J=8.67 Hz), 7.18(2H,d,J=8.79 Hz), 7.25(2H,dd,J=5.25,8.67 Hz),7.86(2H,d,J=8.79 Hz).

Preparation Example 6 (1) Preparation of2-phenyl-4′-(methylthio)-acetophenone

After aluminum chloride (5.61 g, 42.1 mmol) was added to dichloroethane(25 ml), phenylacetyl chloride (5.00 g, 32.3 mmol) and thioanisole (6.03g, 48.5 mmol) were added under ice cooling. The resulting mixture wasstirred at room temperature for 20 hours. Ice water was added to thereaction mixture, followed by extraction with chloroform. The extractwas washed with water and then dried over anhydrous sodium sulfate. Thesolvent was distilled off, and the residue was crystallized with hexane.The crystals were recrystallized from ethanol, whereby the titlecompound (5.77 g, 73.6%) was obtained as colorless prisms. Further, therecrystallization mother liquid was separated and purified bychromatography on a silica gel column [hexane/ethyl acetate (20/1)],whereby the title compound (0.57%, 7.3%) was obtained.

¹H-NMR (CDCl₃) δ: 2.50(3H,s), 4.23(2H,s), 7.20-7.36(7H,m),7.92(2H,d,J=8.8 Hz).

IR (KBr) cm⁻¹: 1682,1587,1334,1221,1090,992,815,706.

(2) Preparation of methyl4-[4-(methylthio)phenyl]-4-oxo-3-phenylbutanoate

Using 2-phenyl-4′-(methylthio)acetophenone as a starting material, theprocedures of Preparation Example 2 were repeated likewise, whereby thetitle compound was obtained in a yield of 86.5%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 82.4-83.0° C.

¹H-NMR (CDCl₃) δ: 2.46(3H,s), 2.70(1H,dd,J=4.95,16.91 Hz),3.36(1H,dd,J=9.65,16.91 Hz), 3.65(3H,s), 5.03(1H,dd,J=4.45,9.65 Hz),7.18(2H,d,J=8.55 Hz), 7.20-7.30(5H,m), 7.88(2H,d,J=8.55 Hz).

IR (KBr) cm⁻¹: 1740,1680,1590,1404,1235,1200,1175,1094.

Preparation Example 7 Preparation of3′-fluoro-4′-methoxy-2-(4-methoxy-phenyl)acetophenone

Thionyl chloride (3.57 g) was added to a solution of4-methoxyphenylacetic acid (3.32 g, 19.98 mmol) in benzene (30 ml).After the mixture was heated under reflux for 3 hours, the solvent wasdistilled off. To the residue, methylene chloride (50 ml) and2-fluoro-anisole (2.10 g) were added. Under ice cooling, aluminumchloride (13.32 g) was added, followed by stirring for 30 minutes. Themixture was then stirred at room temperature for 2 hours. The reactionmixture was added to ice water, followed by extraction with methylenechloride. The extract was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. The residue soobtained was separated and purified by chromatography on a silica gelcolumn and was then crystallized form ethyl acetate-hexane, whereby thetitle compound (2.27 g, 49.6%) was obtained as colorless prisms.

Melting point: 141.7-142.7° C.

Mass (m/Z): 274 (M⁺).

¹H-NMR (CDCl₃) δ: 3.78(3H,s), 3.94(3H,s), 4.15(2H,s), 6.86(2H,d,J=8.7Hz), 6.98(1H,dd,J=8.5 Hz,J=8.5 Hz), 7.17(2H,d,J=8.7 Hz),7.73(1H,dd,J=12.0 Hz,J=2.2 Hz), 7.79(1H,ddd,J=8.5 Hz,J=2.2 Hz,J=1.0 Hz).

IR (KBr) cm⁻¹: 1681,1613,1516,1436,1286,1254,1223,1177,1132,1034,1014,889,809,787.

Preparation Example 8 Preparation of ethyl3-(3-fluoro-4-methoxyphenyl)-4-(4-methoxyphenyl)-4-oxobutanoate: (1)Preparation of 2-(3-fluoro-4-methoxyphenyl)-4′-methoxyacetophenone

Using 3-fluoro-4-methoxyphenylacetic acid and anisole as startingmaterials, the procedures of Preparation Example 7 were repeatedlikewise, whereby the title compound was obtained in a yield of 57.0%.Colorless needles (ethyl acetate-hexane). Melting point: 117.0-117.7° C.Mass (m/Z): 274 (M⁺).

¹H-NMR (CDCl₃) δ: 3.82(3H,s), 3.83(3H,s), 4.13(2H,s), 6.85-7.01(5H,m),7.96(2H,d,J=9.0 Hz).

IR (KBr) cm⁻¹: 1682,1600,1524,1278,1263,1214,1178,1127, 1025.

(2) Preparation of ethyl3-(3-fluoro-4-methoxy-phenyl)-4-(4-methoxyphenyl)-4-oxobutanoate:

Using 2-(3-fluoro-4-methoxyphenyl)-4′-methoxy-acetophenone as a startingmaterial, the procedures of Preparation Example 2 were repeatedlikewise, whereby the title compound was obtained in a yield of 85.5%.Yellow oil.

¹H-NMR (CDCl₃) δ: 1.14(3H,t,J=7.1 Hz) 2.71(1H,dd,J=16.3 Hz,J=5.1 Hz),3.33(1H,dd,J=16.3 Hz,J=9.5 Hz), 3.695(3H,s), 3.703(3H,s),4.06(2H,q,J=7.1 Hz), 5.07(1H,dd,J=9.5 Hz,J=5.1 Hz), 6.77-6.91(3H,m),7.03(1H,d,J=8.3 Hz), 7.10(1H,dd,J=12.0 Hz,J=2.0 Hz), 7.99(2H,d,J=8.8Hz).

Preparation Example 9 Preparation of ethyl3,4-bis(3-fluoro-4-methoxy-phenyl)-4-oxobutanoate (1) Preparation of3′-fluoro-2-(3-fluoro-4-methoxy-phenyl)-4′-methoxyacetophenone

Using 3-fluoro-4-methoxyphenylacetic acid and 2-fluoroanisole asstarting materials, the procedures of Preparation Example 7 wererepeated likewise, whereby the title compound was obtained in a yield of77.5%.

Colorless needles (ethyl acetate-hexane).

Melting point: 150.6-151.7° C.

Mass (m/Z): 292 (M⁺).

¹H-NMR (CDCl₃) δ: 3.87(3H,s), 3.95(3H,s), 4.14(2H,s), 6.88-7.03(4H,m),7.73(1H,dd,J=12.0 Hz,J=2.2 Hz), 7.78(1H,ddd,J=8.5 Hz,J=2.2 Hz,J=1.0 Hz).

IR (KBr) cm⁻¹: 1677,1613,1520,1436,1282,1265,1224,1180, 1124.

(2) Preparation of ethyl3,4-bis(3-fluoro-4-methoxy-phenyl)-4-oxobutanoate

Using 3′-fluoro-2-(3-fluoro-4-methoxyphenyl)-4′-methoxyacetophenone as astarting material, the procedures of Preparation Example 2 were repeatedlikewise, whereby the title compound was obtained in a yield of 62.3%.

Yellow oil.

Mass (m/Z): 378 (M⁺)

¹H-NMR (CDCl₃) δ: 1.18(3H,t,J=7.1 Hz), 2.69(1H,dd,J=17.0 Hz,J=5.1 Hz),3.30(1H,dd,J=17.0 Hz,J=9.5 Hz), 3.81(3H,s), 3.89(3H,s), 4.09(2H,q,J=7.1Hz), 4.94(1H,dd,J=9.5 Hz,J=5.1 Hz), 6.88(1H,dd,J=8.5 Hz,J=8.5 Hz),6.93(1H,dd,J=8.5 Hz,J=8.5 Hz), 6.96-7.06(2H,m), 7.70(1H,dd,J=12.0Hz,J=2.0 Hz), 7.77(1H,d,J=8.5 Hz).

HRMS: Calcd. for C₂₀H₂₀F₂O₅: 378.12785.

-   -   Found: 378.12759.

Example 1 Preparation of5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl)-4,5-dihydro-2H-pyridazin-3-one

Hydrazine hydrate (10.56 g, 210.9 mmol) was added to a solution of ethyl3-(4-chlorophenyl)-4-[4-(methylthio)phenyl]-4-oxobutanoate (42.54 g,117.2 mmol) in ethanol (85 ml), followed by heating under reflux for 15hours at a bath temperature of 100° C. A 4 N aqueous solution of sodiumhydroxide (40 ml) was added to the reaction mixture. After the mixturewas ice-cooled, precipitated crystals were collected by filtration,washed with water (3×100 ml), dried in air, and then dried under reducedpressure (100° C., 2 hours), whereby the title compound (31.49 g, 81.2%)was obtained as pale yellow crystalline powder.

Melting point: 170.5-172.8° C.

Example 2 Preparation of4,5-dihydro-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl)-2H-pyridazin-3-one

Using methyl 3-(4-fluorophenyl)-4-[(4-methyl-thio)phenyl]-4-oxobutanoateas a starting material, the procedures of Example 1 were repeatedlikewise, whereby the title compound was obtained in a yield of 33.1%.

¹H-NMR (CDCl₃) δ: 2.47(3H,s), 2.77(1H,d,J=17.0 Hz),2.99(1H,dd,J=7.73,17.01 Hz), 4.41(1H,d,J=7.73 Hz), 7.00(2H,t,J=8.67 Hz),7.12-7.29(4H,m), 7.59(2H,d,J=8.55 Hz).

Example 3 Preparation of4,5-dihydro-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one

Methyl 4-(4-methoxyphenyl)-4-oxo-3-(4-pyridyl)-butanoate (10.63 g, 35.6mmol) was dissolved in ethanol (200 ml), followed by the addition ofhydrazine hydrate (1.77 g, 35.26 mmol). The mixture was heated underreflux for 17 hours. The reaction mixture was concentrated under reducedpressure. The residue so obtained was separated and purified bychromatography on a silica gel column [silica gel: 100 g,chloroform/methanol (10/1)] and was then recrystallized fromethanol-hexane, whereby the title compound (5.92 g, 59.3%) was obtainedas pale yellow crystalline powder.

Melting point: 100.1-102.3° C.

¹H-NMR (CDCl₃) δ: 2.80(1H,dd,J=1.71,17.09 Hz), 3.04(1H,dd,J=7.81,17.09Hz), 3.82(3H,s), 4.46(1H,dd,J=1.71,7.81 Hz), 6.89(2H,d,J=9.03 Hz),7.15(2H,d,J=6.10 Hz), 7.62(2H,d,J=9.03 Hz), 8.56(2H,d,J=6.10 Hz),8.68(1H,brs).

IR (KBr) cm⁻¹: 1679,1611,1597,1515,1355,1330,1259,1167.

Example 4 Preparation of6-(3,4-dimethoxyphenyl)-5-(4-methoxy-phenyl)-2H-pyridazin-3-one

Using 2-(4-methoxyphenyl)-3′,4′-dimethoxy-acetophenone as a startingmaterial, the procedures of Preparation Example 1 were repeatedlikewise. The reaction product was then recrystallized from ethylacetate-hexane, whereby the title compound was obtained as pale orangecrystals in a yield of 29%.

¹H-NMR (CDCl₃) δ: 3.66(3H,s), 3.81(3H,s), 3.87(3H,s), 6.70(1H,d,J=1.65Hz), 6.75(1H,d,J=8.24 Hz), 6.79(1H,dd,J=1.65,8.25 Hz), 6.94(2H,d,J=8.91Hz), 7.07(2H,d,J=8.90 Hz).

Example 5 Preparation of 6-(4-methoxyphenyl)-5-phenyl-2H-pyridazin-3-one

Using 2-phenyl-4′-methoxyacetophenone (J. Med. Chem., 25, 1070-1077,1982: Martin R. Schneider, Erwin von Angerer, Helmut Schonenberger, RalfTh Michel, and H. F. Fortmeyer) as a starting material, the proceduresof Preparation Example 1 were repeated likewise, whereby the titlecompound was obtained as colorless crystals in a yield of 56.1%.

¹H-NMR (CDCl₃) δ: 1.57-1.69(1H,br), 3.78(3H,s), 6.76(2H,d,J=8.79 Hz),6.97(1H,s), 7.07-7.18(4H,m), 7.24-7.40(3H,m)

Example 6 Preparation of5-(4-chlorophenyl)-6-(4-methoxy-phenyl)-2H-pyridazin-3-one

Using 2-(4-chlorophenyl)-4′-methoxyacetophenone as a starting material,the procedures of Preparation Example 1 were repeated likewise, wherebythe title compound was obtained as pale brown crystals in a yield of11%.

¹H-NMR (CDCl₃) δ: 3.80(3H,s), 6.79(2H,d,J=8.90 Hz), 6.95(1H,s),7.07(2H,d,J=8.90 Hz), 7.10(2H,d,J=8.91 Hz), 7.29(2H,d,J=8.58 Hz),11.73(1H,br).

Example 7 Preparation of5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one

A solution of5-(4-chlorophenyl)-4,5-dihydro-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one(31.49 g, 95.2 mmol) in acetic acid (160 ml) was stirred under heatingat 70° C. After a solution of bromine (15.21 g, 95.2 mmol) in aceticacid (60 ml) was added dropwise over 20 minutes, the mixture wascontinuously stirred under heating for 30 minutes. The reaction mixturewas cooled with ice water, followed by the successive gradual additionof a 10% aqueous solution of sodium hydrogensulfite (50 ml) and water(1.1 l). A precipitate was collected by filtration, washed with water,and then dried in air, whereby pale yellow crystalline powder (33.88 g)was obtained. The powder was suspended in ethyl acetate (120 ml). Thesuspension was heated under reflux at 90° C. for 30 minutes, and hexane(120 ml) was then added. The mixture was cooled with ice water.Precipitated crystals were collected by filtration and then dried inair, whereby title compound (29.84 g, 95.3%) was obtained as pale browncrystalline powder.

Colorless needles (chloroform-hexane)

Melting point: 201.7-203.7° C.

¹H-NMR (CDCl₃) δ: 2.47(3H,s), 6.95(1H,s), 7.05-7.16(6H,m),7.27(2H,d,J=7.3 Hz), 11.40(1H,brs).

IR (KBr) cm⁻¹: 1656,1584,1490,1282,1092.

Example 8 Preparation of6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one

4,5-Dihydro-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one (5.4 g,19.2 mmol) was dissolved in acetic acid (180 ml), followed by theaddition of 2,3-dichloro-5,6-dicyano-1,4-benzoguinone (5.0 g, 22.0mmol). The interior of the reaction system was purged with argon, andthe contents were stirred at 70° C. for 18 hours. The reaction mixturewas concentrated under reduced pressure. The residue was separated andpurified by chromatography on a silica gel column [silica gel: 100 g,chloroform/methanol (10/1)→chloroform/methanol (with 10% (W/W) ammonia)(20/1)], followed by further separation and purification bychromatography on a silica gel column [silica gel: 200 g,chloroform/methanol (with 10% (W/W) ammonia) (20/1)]. The crude crystalswere recrystallized from chloroform-ethyl acetate-diethyl ether, wherebythe title compound (4.61 g, 86.0%) was obtained as pale yellow crystals.

Melting point: 236.0-267.6° C.

¹H-NMR (CDCl₃) δ: 3.80(3H,s), 6.78(2H,d,J=8.79 Hz), 7.03(1H,s),7.08(2H,d,J=6.10 Hz), 7.09(2H,d,J=8.79 Hz), 8.60(2H,d,J=6.10 Hz).

IR (KBr) cm⁻¹: 3236,1672,1605,1515,1254,1176.

Example 9 Preparation of5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one

Using4,5-dihydro-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 8 were repeatedlikewise, whereby the title compound was obtained in a yield of 92.6%.

Pale yellow prisms (ethyl acetate-hexane).

Melting point: 197.4-198.2° C.

Mass (m/e): 312 (M⁺).

¹H-NMR (CDCl₃) δ: 2.47(3H,s), 6.96(1H,s), 7.02(2H,t,J=8.59Hz),7.07-7.13(6H,m).

IR (KBr) cm⁻¹: 3122,1660,1597,1511,1225,1171,1026,852, 818,759,699.

Example 10 Preparation of4,5-dihydro-5-phenyl-6-[4-(methyl-thio)phenyl]-2H-pyridazin-3-one

Using methyl 4-[4-(methylthio)phenyl]-4-oxo-3-phenylbutanoate as astarting material, the procedures of Example 1 were repeated likewise,whereby the title compound was obtained in a yield of 47.5%.

Colorless needles (ethyl acetate-hexane).

Melting point: 212.6-213.8° C.

¹H-NMR (CDCl₃) δ: 2.47(3H,s), 2.81(1H,dd,J=1.65,16.97 Hz),3.01(1H,dd,J=7.88,16.97 Hz), 4.45(1H,dd,J=1.65,7.88 Hz),7.14-7.43(7H,m), 7.61(2H,d,J=8.79 Hz).

Example 11 Preparation of6-[4-(methylthio)phenyl]-5-phenyl-2H-pyridazin-3-one

Using 4,5-dihydro-6-[4-(methylthio)phenyl]-5-phenyl-2H-pyridazin-3-oneas a starting material, the procedures of Example 8 were repeatedlikewise, whereby the title compound was obtained in a yield of 95.7%.

Colorless needles (ethyl acetate-hexane).

Melting point: 185.8-186.1° C.

¹H-NMR (CDCl₃) δ: 2.45(3H,s), 7.04(1H,s), 7.05-7.17(6H,m),7.27-7.40(3H,m).

IR (KBr) cm⁻¹: 1656,1588,1574,1491,1020,894,827,774, 755,701.

Example 12 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-chloro-cinnamyl)-2H-pyridazin-3-one

4-Chlorocinnamyl chloride (898 mg, 4.8 mmol) was added to a suspensionof 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one (802 mg, 2.4 mmol) andpotassium carbonate (663 mg, 4.8 mmol) in N,N-dimethylformamide (8 ml),followed by stirring at 70° C. for 6 hours. After water (50 ml) wasadded to the reaction mixture, the resulting mixture was extracted withethyl acetate. The organic layer was washed successively with water anda saturated aqueous solution of sodium chloride, and then dried overanhydrous sodium sulfate. The solvent was distilled off. An orange oil(1.73 g) so obtained was separated and purified by chromatography on asilica gel column [silica gel: 40 g, hexane/ethyl acetate (1/1)],whereby pale yellow crystalline powder (1.22 g) was obtained. The powderwas recrystallized from chloroform-diethyl ether-hexane, whereby thetitle compound (1.09 g, 91.3%) was obtained as pale yellow prisms (driedat 70° C. for 3 hours under reduced pressure).

Melting point: 155.0-156.7° C.

¹H-NMR (CDCl₃) δ: 3.78(3H,s), 3.80(3H,s), 5.01(2H,dd,J=1.22,6.59 Hz),6.45(1H,dt,J=15.87,6.59 Hz), 6.69(1H,d,J=15.87 Hz), 6.79(2H,d,J=8.79Hz), 6.81(2H,d,J=8.78 Hz), 6.91(1H,s), 7.04(2H,d,J=8.78 Hz),7.13(2H,d,J=8.79 Hz), 7.26(2H,d,J=8.54 Hz), 7.33(2H,d,J=8.79 Hz).

IR (KBr) cm⁻¹: 1665,1609,1513,1246,965,837,700.

Example 13 Preparation of5,6-bis(4-methoxyphenyl)-2-benzyl-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 74.4%.

Colorless prisms (chloroform-hexane).

Melting point: 145.0-145.7° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.80(3H,s), 5.41(2H,s), 6.78(2H,d,J=9.04Hz), 6.80(2H,d,J=8.79 Hz), 6.89(1H,s), 7.02(2H,d,J=8.79 Hz),7.11(2H,d,J=8.79 Hz), 7.11(2H,d,J=8.78 Hz), 7.27-7.40(3H,m),7.50-7.60(2H,m).

IR (KBr) cm⁻¹: 1659,1608,1515,1293,1249,1186,1177,1029, 841,702.

Example 14 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-methoxybenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4methoxyphenyl)-2H-pyridazin-3-one as a starting material,the procedures of Example 12 were repeated likewise, whereby the titlecompound was obtained in a yield of 54.54%.

Colorless prisms (methanol-diethyl ether).

Melting point: 171-172° C.

¹H-NMR (CDCl₃) δ: 3.79(9H,s), 5.35(2H,s), 6.78(2H,d,J=8.79 Hz),6.83(2H,d,J=8.79 Hz), 6.87(1H,s), 6.88(2H,d,J=8.79 Hz), 7.01(2H,d,J=8.79Hz), 7.11(2H,d,J=9.04 Hz), 7.69(2H,d,J=8.79 Hz).

IR (KBr) cm⁻¹: 1664,1609,1512,1247,1185,1173,1023,951.

Example 15 Preparation of5,6-bis(4-methoxyphenyl)-2-(3,4-dimethoxybenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 17.4%.

Pale yellow amorphous.

Mass (m/e): 458 (M⁺).

¹H-NMR (CDCl₃) δ: 3.79(6H,s), 3.87(3H,s), 3.90(3H,s), 5.32(2H,s),6.78(2H,d,J=8.79 Hz), 6.80(2H,d,J=8.79 Hz), 6.85(1H,d,J=8.30 Hz),6.88(1H,s), 6.96(2H,d,J=8.79 Hz), 7.10-7.14(1H,m), 7.11(2H,d,J=8.79 Hz),7.17(1H,d,J=1.95 Hz).

IR (film) cm⁻¹: 1660,1609,1515,1250,1028,834.

Example 16 Preparation of5,6-bis(4-methoxyphenyl)-2-(3,4,5-trimethoxybenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 73.6%.

Pale yellow prisms (chloroform-diethyl ether).

Melting point: 138.0-139.0° C.

¹H-NMR (CDCl₃) δ: 3.80(6H,s), 3.84(3H,s), 3.87(3H,s), 5.33(2H,s),6.78(2H,d,J=8.79 Hz), 6.80(2H,d,J=8.79 Hz), 6.82(2H,s), 6.89(1H,s),7.02(2H,d,J=8.79 Hz), 7.11(2H,d,J=8.76 Hz).

IR (KBr) cm⁻¹: 1658,1607,1590,1511,1250,1130,1118,840.

Example 17 Preparation of5,6-bis(4-methoxyphenyl)-2-phenethyl-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 80.0%.

Pale yellow needles (chloroform-hexane).

Melting point: 139.8-140.4° C.

¹H-NMR (CDCl₃) δ: 3.17-3.23(2H,m), 3.79(3H,s), 3.81(3H,s),4.46-4.52(2H,m), 6.77(2H,d,J=8.79 Hz), 6.81(2H,d,J=9.03 Hz), 6.90(1H,s),7.02(2H,d,J=9.03 Hz), 7.03(2H,d,J=9.03 Hz), 7.24-7.33(5H,m).

IR (KBr) cm⁻¹: 1654,1608,1512,1245,1177,1029,843,743.

Example 18 Preparation of5,6-bis(4-methoxyphenyl)-2-(3,4-dimethoxyphenethyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 77.0%.

Pale yellow needles (ethyl acetate-hexane).

Melting point: 130.9-131.4° C.

¹H-NMR (CDCl₃) δ: 3.12-3.17(2H,m), 3.79(3H,s), 3.81(3H,s), 3.84(3H,s),3.87(3H,s), 4.44-4.50(2H,m), 6.76-6.85(7H,m), 6.91(1H,s),7.02(2H,d,J=9.03 Hz), 7.04(1H,s), 7.05(2H,d,J=9.04 Hz).

IR (KBr) cm⁻¹: 1655,1608,1516,1266,1242,1028,842.

Example 19 Preparation of5,6-bis(4-methoxyphenyl)-2-(3-phenylpropyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 81.3%.

Brown amorphous.

¹H-NMR (CDCl₃) δ: 2.18-2.30(2H,m), 2.76(2H,t,J=8.30 Hz), 3.79(3H,s),3.80(3H,s), 4.31(2H,t,J=8.32 Hz), 6.78(2H,d,J=9.04 Hz), 6.81(2H,d,J=8.79Hz), 6.86(1H,s), 7.03(2H,d,J=8.79 Hz) 7.12(2H,d,J=9.03 Hz),7.15-7.30(5H,m).

IR (film) cm⁻¹: 1652,1608,1515,1295,1247,1177,1031,833, 750,700.

Example 20 Preparation of5,6-bis(4-methoxyphenyl)-2-[3-(phenoxy)propyl]-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was, obtained in a yield of 75.5%.

Pale yellow crystalline powder (diethyl ether).

Melting point: 110.0-111.0° C.

Mass (m/e): 442 (M⁺).

¹H-NMR (CDCl₃) δ: 2.37-2.42(2H,m), 3.78(3H,s), 3.81(3H,s),4.12(2H,t,J=6.35 Hz), 4.47(2H,t,J=7.08 Hz), 6.74(2H,d,J=8.79 Hz),6.81(2H,d,J=8.79 Hz), 6.88-6.97(4H,m), 7.03(4H,d,J=9.04 Hz),7.24-7.30(2H,m).

IR (KBr) cm⁻¹: 1660,1609,1513,1295,1250,1176,1027,838, 753.

Example 21 Preparation of5,6-bis(4-methoxyphenyl)-2-cinnamyl-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 50.4%.

Yellow amorphous.

Mass (m/e): 424 (M⁺).

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.80(3H,s), 5.01(2H,dd,J=0.98,6.59 Hz),6.48(1H,dt,J=15.87,6.59 Hz), 6.74(1H,d,J=15.87 Hz), 6.78(2H,d,J=9.03Hz), 6.81(2H,d,J=8.79 Hz), 6.91(1H,s), 7.04(2H,d,J=8.78 Hz),7.13(2H,d,J=9.03 Hz), 7.20-7.33(3H,m), 7.37-7.42(2H,m).

IR (KBr) cm⁻¹: 1660,1609,1511,1295,1248,1177,1027,950, 833.

Example 22 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-methoxycinnamyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 16.1%.

Pale yellow oil.

Mass (m/e): 454 (M⁺).

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.80(3H,s), 4.98(2H,d,J=6.59 Hz),6.35(1H,dt,J=15.87,6.59 Hz), 6.70(1H,d,J=15.8 Hz), 6.78(2H,d,J=9.03 Hz),6.81(2H,d,J=9.03 Hz), 6.84(2H,d,J=9.03 Hz), 6.91(1H,s), 7.04(2H,d,J=9.04Hz), 7.13(2H,d,J=8.79 Hz), 7.34(2H,d,J=8.79 Hz).

IR (film) cm⁻¹: 1652,1608,1514,1297,1248,1177,1031,834, 754.

Example 23 Preparation of5,6-bis(4-methoxyphenyl)-2-[3-(4-methoxyphenyl)propyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 59.4%.

Pale yellow amorphous.

Mass (m/e): 456 (M⁺).

¹H-NMR (CDCl₃) δ: 2.16-2.27(2H,m), 2.70(2H,t,J=7.32 Hz), 3.77(3H,s),3.80(3H,s), 3.81(3H,s), 4.29(2H,t,J=7.32 Hz), 6.79(2H,d,J=8.79 Hz),6.81(4H,d,J=8.79 Hz), 6.87(1H,s), 7.03(2H,d,J=9.03 Hz), 7.12(2H,d,J=8.79Hz), 7.15(2H,d,J=7.81 Hz).

IR (film) cm⁻¹: 1661,1609,1514,1297,1247,1179,1034,833, 754.

Example 24 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-methyl-cinnamyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 71.6%.

Pale brown oil.

¹H-NMR (CDCl₃) δ: 2.33(3H,s), 3.79(3H,s), 3.80(3H,s), 5.00(2H,d,J=6.59Hz), 6.42(1H,dt,J=15.87,6.60 Hz), 6.72(1H,d,J=15.87 Hz),6.78(2H,d,J=8.78 Hz), 6.81(2H,d,J=8.79 Hz), 6.91(1H,s), 7.04(2H,d,J=8.78Hz), 7.11(2H,d,J=7.32 Hz), 7.13(2H,d,J=9.04 Hz), 7.30(2H,d,J=8.06 Hz).

IR (film) cm⁻¹: 1652,1610,1514,1296,1251,1180,1034,834, 756.

Example 25 Preparation of5,6-bis(4-methoxyphenyl)-2-[3-(4-methylphenyl)propyl]-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 30.4%.

Pale yellow oil.

¹H-NMR (CDCl₃) δ: 2.22(2H,quintet,J=7.32 Hz), 2.30(3H,s),2.72(2H,t,J=7.33 Hz), 3.79(3H,s), 3.80(3H,s), 4.30(2H,t,J=7.32 Hz),6.78(2H,d,J=8.78 Hz), 6.80(2H,d,J=8.79 Hz), 6.86(1H,s), 7.23(2H,d,J=8.79Hz), 7.09(2H,d,J=5.86 Hz), 7.11(2H,d,J=9.03 Hz).

IR (film) cm⁻¹: 1652,1610,1514,1296,1247,1179,1033,833, 807,755.

Example 26 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-fluorobenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 56.8%.

Pale yellow needles (diethyl ether-hexane).

Melting point: 132.3-132.9° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.80(3H,s), 5.37(2H,s), 6.78(2H,d,J=8.78Hz), 6.80(2H,d,J=9.03 Hz), 7.02(2H,d,J=9.03 Hz).

IR (KBr) cm⁻¹: 1665,1609,1515,1294,1247,1184,1177,1027, 839.

Example 27 Preparation of5,6-bis(4-methoxyphenyl)-2-(2,4-difluorobenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 88.4%.

Pale yellow needles (ethyl acetate-hexane).

Melting point: 150.1-150.9° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.81(3H,s), 5.44(2H,s), 6.77(2H,d,J=8.79Hz), 6.81(2H,d,J=8.79 Hz), 6.83-6.88(2H,m), 6.89(1H,s), 7.04(2H,d,J=8.78Hz), 7.09(2H,d,J=9.03 Hz), 7.42-7.51(1H,m).

IR (KBr) cm⁻¹: 1667,1608,1512,1502,1292,1252,1243,1181, 840,831.

Example 28 Preparation of5,6-bis(4-methoxyphenyl)-2-(3-fluoro-4-methoxybenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 84.3%.

Pale yellow scales (ethyl acetate-diethyl ether).

Melting point: 166.5-167.5° C.

¹H-NMR (CDCl₃) δ: 3.80(6H,s), 3.87(3H,s), 5.32(2H,s), 6.77-6.82(1H,m),6.78(2H,d,J=9.03 Hz), 6.79(2H,d,J=8.79 Hz), 6.88(1H,s), 6.90-6.96(1H,m),7.02(2H,d,J=8.79 Hz), 7.11(2H,d,J=8.78 Hz), 7.27-7.32(1H,m).

IR (KBr) cm⁻¹: 1662,1609,1516,1275,1248,1183,837.

Example 29 Preparation of5,6-bis(4-methoxyphenyl)-2-(3,4-difluorobenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 51.6%.

Pale yellow prisms (ethyl acetate-diethyl ether).

Melting point: 155.4-156.1° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.80(3H,s), 5.34(2H,s), 6.79(2H,d,J=8.79Hz), 6.80(2H,d,J=8.79 Hz), 6.89(1H,s), 7.03(2H,d,J=9.03 Hz),7.08-7.18(1H,m), 7.10(2H,d,J=8.79 Hz), 7.23-7.31(1H,m), 7.33-7.40(1H,m).

IR (KBr) cm⁻¹: 1660,1610,1516,1293,1286,1251,1241,1134, 1030,847.

Example 30 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-fluorocinnamyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 41.0%.

Pale yellow amorphous.

Mass (m/e): 442 (M⁺).

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.80(3H,s), 5.00(2H,d,J=6.84 Hz),6.40(1H,dt,J=15.87,6.60 Hz), 6.71(1H,d,J=15.86 Hz), 6.79(2H,d,J=8.79Hz), 6.81(2H,d,J=9.03 Hz), 6.91(1H,s), 6.96-7.06(4H,m), 7.14(2H,d,J=9.04Hz), 7.34-7.39(2H,m).

IR (KBr) cm⁻¹: 1660,1609,1509,1296,1249,1178,1027,833.

Example 31 Preparation of5,6-bis(4-methoxyphenyl)-2-(2,4-difluorocinnamyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 34.8%.

Colorless needles(ethyl acetate-diethyl ether).

Melting point: 107.3-108.1° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.81(3H,s), 5.01(2H,d,J=6.35 Hz),6.49(1H,dt,J=15.86,6.60 Hz), 6.74-6.84(3H,m), 6.79(2H,d,J=8.78 Hz),6.81(2H,d,J=8.79 Hz), 6.91(1H,s), 7.04(2H,d,J=8.78 Hz), 7.14(2H,d,J=8.78Hz), 7.39-7.48(1H,m).

IR (KBr) cm⁻¹: 1664,1608,1508,1252,1244,1180,1034,973, 925,833. Example32 Preparation of5,6-bis(4-methoxyphenyl)-2-(3-(2,4-difluorophenyl)propyl]-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 83.7%.

Yellow amorphous.

Mass (m/e): 462 (M⁺).

¹H-NMR (CDCl₃) δ: 2.22(2H,q,J=7.57 Hz), 2.57(2H,t,J=7.56 Hz),3.80(3H,s), 3.81(3H,s), 4.30(2H,t,J=7.57 Hz), 6.72-6.83(2H,m),6.79(2H,d,J=8.79 Hz), 6.81(2H,d,J=8.79 Hz), 6.87(1H,s), 7.03(2H,d,J=8.79Hz), 7.12(2H,d,J=8.79 Hz), 7.16-7.22(1H,m).

IR (film) cm⁻¹: 1660,1608,1512,1296,1250,1178,834.

Example 33 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-chlorobenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 89.2%.

Pale yellow powder (chloroform-diethyl ether).

Melting point: 124.2-127.3° C.

Mass (m/e): 432 (M⁺).

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.80(3H,s), 5.36(2H,s), 6.78(2H,d,J=8.79Hz), 6.80(2H,d,J=9.03 Hz), 6.88(1H,s), 7.02(2H,d,J=8.79 Hz),7.06(2H,d,J=9.04 Hz), 7.31(2H,d,J=8.30 Hz), 7.47(2H,d,J=8.30 Hz).

IR (KBr) cm⁻¹: 1667,1609,1513,1249,1184,1176,835.

Example 34 Preparation of5,6-bis(4-methoxyphenyl)-2-(2,4-dichlorobenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 67.7%.

Slightly yellowish needles (chloroform-diethyl ether).

Melting point: 140.7-141.2° C.

¹H-NMR (CDCl₃) δ: 3.78(3H,s), 3.81(3H,s), 5.31(2H,s), 6.76(2H,d,J=8.79Hz), 6.82(2H,d,J=8.79 Hz), 6.93(1H,s), 7.06(2H,d,J=8.79 Hz),7.09(2H,d,J=9.03 Hz), 7.22-7.23(2H,m), 7.43(1H,d,J=1.71 Hz).

IR (KBr) cm⁻¹: 1664,1608,1587,1512,1468,1252,1181,1032, 834,696.

Example 35 Preparation of5,6-bis(4-methoxyphenyl)-2-(3,4-dichlorobenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 56.4%.

Colorless scales (ethyl acetate-hexane).

Melting point: 107.8-109.5° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.80(3H,s), 5.34(2H,s), 6.79(2H,d,J=8.79Hz), 6.81(2H,d,J=8.79 Hz), 6.89(1H,s), 7.03(2H,d,J=9.03 Hz),7.10(2H,d,J=9.04 Hz), 7.37(1H,dd,J=1.95,8.30 Hz), 7.42(1H,d,J=8.06 Hhz),7.63(1H,d,J=1.71 Hz).

IR (KBr) cm⁻¹: 1661,1609,1514,1471,1293,1248,1182,1024, 834.

Example 36 Preparation of5,6-bis(4-methoxyphenyl)-2-(2,6-dichlorobenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 70.0%.

Yellow needles (diethyl ether).

Melting point: 144.0-144.5° C.

¹H-NMR (CDCl₃) δ: 3.75(3H,s), 3.80(3H,s), 5.70(2H,s), 6.67(2H,d,J=8.78Hz), 6.81(2H,d,J=9.28 Hz), 6.92(2H,d,J=9.28 Hz), 7.04(2H,d,J=8.79 Hz),7.21(1H,dd,J=7.32,8.79 Hz).

IR (KBr) cm⁻¹: 1664,1608,1513,1290,1254,1182,1027,834, 786.

Example 37 Preparation of5,6-bis(4-methoxyphenyl)-2-(2,4,6-trichlorobenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 28.5%.

Slight yellow needles (diethyl ether-hexane).

Melting point: 142.1-142.7° C.

¹H-NMR (CDCl₃) δ: 3.76(3H,s), 3.81(3H,s), 5.65(2H,s), 6.70(2H,d,J=9.03Hz), 6.81(2H,d,J=9.03 Hz), 6.89(1H,s), 6.94(2H,d,J=9.04 Hz),6.94(2H,d,J=9.03 Hz), 7.37(2H,s).

IR (KBr) cm⁻¹: 1663,1609,1512,1248,1177,1026,838,787.

Example 38 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-chlorophenethyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 67.4%.

Pale yellow needles (ethyl acetate-hexane).

Melting point: 133.0-134.0° C.

¹H-NMR (CDCl₃) δ: 3.17(2H,t,J=7.81 Hz), 3.80(3H,s), 3.81(3H,s),4.46(2H,t,J=7.81 Hz), 6.78(2H,d,J=8.79 Hz), 6.81(2H,d,J=8.79 Hz),6.89(1H,s), 7.01(2H,d,J=8.79 Hz), 7.02(2H,d,J=8.79 Hz), 7.22(2H,d,J=8.79Hz), 7.28(2H,d,J=8.54 Hz).

IR (KBr) cm⁻¹: 1648,1608,1514,1297,1252,1175,836.

Example 39 Preparation of5,6-bis(4-methoxyphenyl)-2-(2,4-dichlorophenethyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 80.2%.

Pale yellow prisms (diethyl ether-hexane).

Melting point: 119.4-120.1° C.

¹H-NMR (CDCl₃) δ: 3.30(2H,t,J=7.08 Hz), 3.79(3H,s), 3.81(3H,s),4.51(2H,t,J=7.08 Hz), 6.76(2H,d,J=9.03 Hz), 6.81(2H,d,J=9.03 Hz),6.87(1H,s), 6.96(2H,d,J=8.79 Hz), 7.02(2H,d,J=8.79 Hz), 7.18(2H,d,J=1.71Hz), 7.40(1H,d,J=1.71 Hz).

IR (KBr) cm⁻¹: 1660,1607,1513,1294,1249,1185,832.

Example 40 Preparation of5,6-bis(4-methoxyphenyl)-2-(2,4-dichlorocinnamyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 74.5%.

Pale yellow amorphous.

Mass (m/e): 492,494(M⁺).

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.81(3H,s), 5.04(2H,dd,J=1.46,6.59 Hz),6.46(1H,dt,J=15.87,6.59 Hz), 6.78(2H,d,J=8.78 Hz), 6.81(2H,d,J=8.79 Hz),6.92(1H,s), 7.04(1H,d,J=15.87 Hz), 7.05(2H,d,J=9.03 Hz),7.19(1H,dd,J=2.19,8.55 Hz), 7.37(1H,d,J=2.20 Hz), 7.84(1H,d,J=8.54 Hz).

IR (KBr) cm⁻¹: 1664,1609,1512,1469,1248,950,833,746.

Example 41 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-nitrobenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 86.2%.

Pale brown crystals.

¹H-NMR (CDCl₃) δ: 3.80(3H,s), 3.81(3H,s), 5.49(2H,s), 6.79(2H,d,J=8.79Hz), 6.81(2H,d,J=8.79 Hz), 6.91(1H,s), 7.03(2H,d,J=8.79 Hz),7.10(2H,d,J=8.79 Hz), 8.21(2H,d,J=8.79 Hz).

IR (KBr) cm⁻¹: 1664,1609,1522,1347,1247,1185,1025,835.

Example 42 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-methoxycarbonylbenzyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 78.8%.

Colorless needles (ethyl acetate-hexane).

Melting point: 185.5-186.6° C.

Mass (m/e): 456 (M⁺).

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.80(3H,s), 3.91(3H,s), 5.45(2H,s),6.78(2H,d,J=8.79 Hz), 6.80(2H,d,J=9.04 Hz), 6.90(1H,s), 7.03(2H,d,J=8.79Hz), 7.09(2H,d,J=9.03 Hz), 7.56(2H,d,J=8.06 Hz), 8.06(2H,d,J=8.54 Hz).

IR (KBr) cm⁻¹: 1722,1659,1608,1565,1514,1249,1183,1113, 1021,835.

Example 43 Preparation of5,6-bis(4-methoxyphenyl)-2-(2-pyridylmethyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 63.1%.

Slight yellow prisms (chloroform-diethyl ether-hexane).

Melting point: 116.0-117.0° C.

Mass (m/e): 399 (M⁺).

¹H-NMR (CDCl₃) δ: 3.78(3H,s), 3.81(3H,s), 5.58(2H,s), 6.76(2H,d,J=8.79Hz), 6.82(2H,d,J=9.04 Hz), 6.95(1H,s), 7.06(2H,d,J=8.79 Hz),7.12(2H,d,J=8.79 Hz), 7.20(1H,dd,J=4.87,7.56 Hz), 7.30(1H,d,J=7.81 Hz),7.66(1H,dt,J=1.71,7.81 Hz), 8.59(1H,d,J=4.88 Hz).

IR (KBr) cm⁻¹: 1656,1608,1514,1246,1176,1027,843.

In a manner known per se in the art, the hydrochloride of the titlecompound was obtained in a yield of 96.4%.

Pale yellow amorphous.

¹H-NMR (CDCl₃) δ: 3.73(3H,s), 3.76(3H,s), 5.54(2H,s), 6.84(2H,d,J=8.79Hz), 6.90(2H,d,J=8.79 Hz), 6.95(1H,s), 7.08(2H,d,J=8.79 Hz),7.14(2H,d,J=8.79 Hz), 7.54(1H,d,J=7.82 Hz), 8.06(1H,m), 8.66(1H,d,J=4.64Hz).

IR (KBr) cm⁻¹: 1661,1609,1512,1297,1250,1177,1026,835.

Example 44 Preparation of5,6-bis(4-methoxyphenyl)-2-(3-pyridylmethyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 71.4%.

Pale yellow prisms (chloroform-diethyl ether).

Melting point: 167.4-168.4° C.

Mass (m/e): 399 (M⁺).

¹H-NMR (CDCl₃) δ: 3.80(3H,s), 5.42(2H,s), 6.78(2H,d,J=8.79 Hz),6.80(2H,d,J=9.03 Hz), 6.89(1H,s), 7.02(2H,d,J=8.79 Hz), 7.11(2H,d,J=8.79Hz), 7.29(1H,dd,J=4.88,7.81 Hz), 7.88(1H,td,J=1.71,7.81 Hz),8.56(1H,dd,J=1.71,4.88 Hz), 8.79(1H,d,J=1.47 Hz).

IR (KBr) cm⁻¹: 1669,1608,1514,1294,1249,1183,839.

In a manner known per se in the art, the methane-sulfonate of the titlecompound was obtained in a yield of 89.1%.

Colorless prisms (methanol-diethyl ether)

Melting point: 214.2-214.8° C.

¹H-NMR (CDCl₃+CD₃OD) δ: 2.89(3H,s), 3.81(6H,s), 5.55(2H,s),6.80(2H,d,J=9.03 Hz), 6.82(2H,d,J=8.79 Hz), 6.91(1H,s), 7.04(2H,d,J=9.03Hz), 7.11(2H,d,J=8.79 Hz), 7.92(2H,dd,J=5.86,8.05 Hz), 8.63(1H,d,J=8.31Hz), 8.93(1H,d,J=5.61 Hz), 8.98(1H,brs).

IR (KBr) cm⁻¹: 1655,1603,1515,1243,1156,1034,840.

Example 45 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-pyridylmethyl)-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 76.0%.

Orange prisms (chloroform-diethyl ether).

Melting point: 182.1-183.1° C.

Mass (m/e): 399 (M⁺).

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.81(3H,s), 5.40(2H,s), 6.78(2H,d,J=8.78Hz), 6.81(2H,d,J=8.06 Hz), 6.92(1H,s), 7.04(2H,dd,J=2.20,9.03 Hz),7.10(2H,dd,J=2.20,8.79 Hz), 7.36(2H,dd,J=1.71,6.10 Hz),8.59(2H,dd,J=1.71,6.10 Hz).

IR (KBr) cm⁻¹: 1660,1610,1513,1294,1247,1174,1028,845.

In a manner known per se in the art, the methane-sulfonate of the titlecompound was obtained in a yield of 86.0%.

Slight yellow prisms (methanol-diethyl ether).

Melting point: 219.0-221.0° C. (decomposed)

¹H-NMR (CD₃OD) δ: 2.70(3H,s), 3.77(3H,s), 3.79(3H,s), 5.73(2H,s),6.82(2H,d,J=8.79 Hz), 6.88(2H,d,J=8.79 Hz), 7.00(1H,s), 7.13(2H,d,J=9.03Hz), 7.15(2H,d,J=8.79 Hz), 8.07(2H,d,J=6.84 Hz), 8.83(2H,d,J=6.83 Hz).

IR (KBr) cm⁻¹: 1656,1603,1514,1298,1245,1178,1163,1035, 840.

Example 46 Preparation of6-(4-methoxyphenyl)-5-phenyl-2-cinnamyl-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-phenyl-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 12 were repeated likewise, wherebythe title compound was obtained in a yield of 73.9%.

Orange prisms (ethyl acetate-hexane).

Melting point: 135.8-137.1° C.

¹H-NMR (CDCl₃) δ: 3.78(3H,s), 5.02(2H,dd,J=0.98,6.67 Hz),6.50(1H,dt,J=15.86,6.67 Hz), 6.71-6.80(3H,m), 6.94(1H,s),7.06-7.15(4H,m), 7.20-7.34(6H,m), 7.36-7.44(2H,m).

IR (KBr) cm⁻¹: 1664,1609,1517,1250,1182,1023,965,840.

Example 47 Preparation of6-(3,4-dimethoxyphenyl)-5-(4-methoxy-phenyl)-2-(2,4-dichlorobenzyl)-2H-pyridazin-3-one

Using 6-(3,4-dimethoxyphenyl)-5-(4-methoxy-phenyl)-2H-pyridazin-3-one asa starting material, the procedures of Example 12 were repeatedlikewise, whereby the title compound was obtained in a yield of 69.5%.

Colorless needles (ethyl acetate-hexane).

Melting point: 118.6-119.8° C.

¹H-NMR (CDCl₃) δ: 3.18(2H,t,J=7.32 Hz), 3.63(3H,s), 3.80(3H,s),3.87(3H,s), 4.48(2H,t,J=7.32 Hz), 6.52(1H,d,J=1.95 Hz),6.67(1H,dd,J=1.95,8.30 Hz), 6.76(1H,d,J=8.30 Hz), 6.81(2H,d,J=9.03 Hz),6.91(1H,s), 7.03(2H,d,J=8.79 Hz), 7.21(2H,d,J=8.55 Hz), 7.28(2H,d,J=8.54Hz).

IR (KBr) cm¹: 1668,1519,1513,1469,1270,1253,1175,1140.

Example 48 Preparation of6-(3,4-dimethoxyphenyl)-5-(4-methoxy-phenyl)-2-(4-chlorophenethyl)-2H-pyridazin-3-one

Using 6-(3,4-dimethoxyphenyl)-5-(4-methoxy-phenyl)-2H-pyridazin-3-one asa starting material, the procedures of Example 12 were repeatedlikewise, whereby the title compound was obtained in a yield of 87.0%.

Pale yellow amorphous.

Mass (m/e): 476 (M⁺).

¹H-NMR (CDCl₃) δ: 3.62(3H,s), 3.81(3H,s), 3.86(3H,s), 5.52(2H,s),6.65(1H,s), 6.73(2H,d,J=1.22 Hz), 6.83(2H,d,J=8.79 Hz), 6.94(1H,s),7.07(2H,d,J=8.79 Hz), 7.22(1H,dd,J=1.95,8.30 Hz), 7.30(1H,d,J=8.30 Hz),7.44(1H,d,J=2.20 Hz).

IR (KBr) cm⁻¹: 1660,1608,1512,1267,1251,1218,1175,1027, 834.

Example 49 Preparation of5-(4-chlorophenyl)-6-(4-methoxy-phenyl)-2-benzyl-2H-pyridazin-3-one

Using 5-(4-chlorophenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one as astarting material, the procedures of Example 12 were repeated likewise,whereby the title compound was obtained in a yield of 65.5%.

Pale yellow prisms (diethyl ether-hexane).

Melting point: 165.0-167.0° C.

Mass (m/e): 402,404 (M⁺).

¹H-NMR (CDCl₃) δ: 3.80(3H,s), 5.42(2H,s), 6.79(2H,d,J=8.79 Hz),6.89(1H,s), 7.03(2H,d,J=8.79 Hz), 7.08(2H,d,J=9.04 Hz), 7.27(2H,d,J=8.79Hz), 7.29-7.40(3H,m), 7.52(2H,dd,J=1.71,8.06 Hz).

IR (KBr) cm⁻¹: 1672,1608,1515,1248,1184,833.

Example 50 Preparation of5-(4-chlorophenyl)-6-(4-methoxy-phenyl)-2-(4-pyridylmethyl)-2H-pyridazin-3-one

Using 5-(4-chlorophenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one as astarting material, the procedures of Example 12 were repeated likewise,whereby the title compound was obtained in a yield of 73.2%.

Slightly pale yellow prisms (diethyl ether).

Melting point: 142.0-143.0° C.

Mass (m/e): 403,405 (M⁺).

¹H-NMR (CDCl₃) δ: 3.80(3H,s), 5.41(2H,s), 6.79(2H,dd,J=2.20,8.79 Hz),6.95(1H,s), 7.06(2H,dd,J=1.95,8.54 Hz), 7.07(2H,dd,J=2.20,9.03 Hz),7.29(2H,dd,J=1.95,8.55 Hz), 7.36(2H,dd,J=1.71,6.11 Hz),8.60(2H,dd,J=1.71,6.11 Hz).

IR (KBr) cm⁻¹: 1660,1601,1587,1514,1247,1174,1091,953, 844,789.

In a manner known per se in the art, the methane-sulfonate of the titlecompound was obtained in a yield of 66.8%.

Colorless prisms (methanol-ethyl acetate).

Melting point: 201.5-203.0° C.

¹H-NMR (CDCl₃) δ: 2.89(3H,s), 3.81(3H,s), 5.60(2H,s), 6.80(2H,d,J=8.79Hz), 6.97(1H,s), 7.06(2H,d,J=9.04 Hz), 7.07(2H,d,J=8.79 Hz),7.31(2H,d,J=8.79 Hz), 7.95(2H,d,J=6.83 Hz), 8.88(2H,d,J=6.83 Hz).

IR (KBr) cm⁻¹: 1662,1609,1515,1247,1209,1192,1179,1036, 842,785.

Example 51 Preparation of2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

5-(4-Chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (500 mg,1.52 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 ml),followed by the addition of potassium carbonate (420 mg, 3.04 mmol).Benzyl bromide (286 mg, 1.67 mmol) was then added at 50° C., and themixture was stirred at 70° C. for 40 minutes. After the temperature ofthe reaction mixture was allowed to cool down to room temperature, thereaction mixture was diluted with ethyl acetate. The mixture was washedwith water and then with a brine, and was then dried over anhydroussodium sulfate. The solvent was distilled off. The residue so obtainedwas separated and purified by chromatography on a silica gel column[hexane/ethyl acetate (3/1)], whereby pale yellow crystals wereobtained. The crystals were recrystallized from ethyl acetate-hexane,whereby the title compound (552.6 mg, 86.8%) was obtained as pale yellowprisms.

Melting point: 155.0-155.6° C.

Mass (m/e): 418,420 (M⁺).

¹H-NMR (CDCl₃) δ: 2.46(3H,s), 5.42(2H,s), 6.90(1H,s), 7.04(2H,d,J=8.40Hz), 7.06(2H,d,J=8.40 Hz), 7.11(2H,d,J=8.59 Hz), 7.27(2H,d,J=8.40 Hz),7.31-7.38(3H,m), 7.53(2H,d,J=6.83 Hz).

IR (KBr) cm⁻¹: 3032,2925,1669,1581,1493,1095,950,829, 695.

Example 52 Preparation of5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2-cyclopropylmethyl-2H-pyridazin-3-one

Using 5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 51 were repeatedlikewise, whereby the title compound was obtained in a yield of 84.0%.

Pale yellow crystalline powder (diethyl ether).

Melting point: 142.0-143.0° C.

Mass (m/e): 382,384 (M⁺).

¹H-NMR (CDCl₃) δ: 0.48-0.61(4H,m), 1.42-1.48(1H,m), 2.47(3H,s),4.12(2H,d,J=7.42 Hz), 6.91(1H,s), 7.08(2H,d,J=8.40 Hz), 7.10(2H,d,J=7.62Hz), 7.13(2H,d,J=8.79 Hz), 7.29(2H,d,J=8.40 Hz).

IR (KBr) cm⁻¹: 1664,1598,1583,1493,1092,952,829.

Example 53 Preparation of5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2-(2,4-difluorobenzyl)-2H-pyridazin-3-one

Using 5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 51 were repeatedlikewise, whereby the title compound was obtained in a yield of 79.0%.

Pale yellow prisms (ethyl acetate-hexane).

Melting point: 157.4-157.5° C.

Mass (m/e): 454,456 (M⁺).

¹H-NMR (CDCl₃) δ: 2.46(3H,s), 5.45(2H,s), 6.82(2H,m), 6.91(1H,s),7.03-7.07(4H,m), 7.12(2H,d,J=8.40 Hz), 7.29(2H,d,J=8.40 Hz),7.45-7.51(1H,m).

IR (KBr) cm⁻¹: 1672,1600,1506,1274,1140,1093,972,829.

Example 54 Preparation of5-(4-chlorophenyl)-6-(4-(methylthio)-phenyl]-2-(2,4-dichlorobenzyl)-2H-pyridazin-3-one

Using 5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 51 were repeatedlikewise, whereby the title compound was obtained in a yield of 97.1%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 154.5-155.0° C.

Mass (m/e): 486,488,490 (M⁺).

¹H-NMR (CDCl₃) δ: 2.46(3H,s), 5.51(2H,s), 6.94(1H,s), 7.04(2H,d,J=8.55Hz), 7.09(2H,d,J=8.55 Hz), 7.08(2H,d,J=8.79 Hz), 7.22(1H,dd,J=8.30,1.83Hz), 7.24-7.33(3H,m), 7.43(1H,d,J=1.83 Hz).

IR (KBr) cm⁻¹: 1660,1585,1484,1095,829,819.

Example 55 Preparation of5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2-(3-pyridylmethyl)-2H-pyridazin-3-one

Using 5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 51 were repeatedlikewise, whereby the title compound was obtained in a yield of 65.6%.

Pale yellow prisms (ethyl acetate-hexane).

Melting point: 148.4-148.5° C.

Mass (m/e): 419 (M⁺).

¹H-NMR (CDCl₃) δ: 2.47(3H,s), 5.42(2H,s), 6.91(1H,s), 7.03-7.13(6H,m),7.27-7.32(3H,m), 7.88(1H,tt,J=7.81,1.95 Hz), 8.57(1H,dd,J=4.88,1.71 Hz),8.79(1H,d,J=1.95 Hz).

IR (KBr) cm⁻¹: 1665,1580,1490,1428,1311,1093,834.

Example 56 Preparation of5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2-cinnamyl-2H-pyridazin-3-one

Using 5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 51 were repeatedlikewise, whereby the title compound was obtained in a yield of 73.9%.

Colorless prisms (chloroform-hexane).

Melting point: 109.3-110.2° C.

Mass (m/e): 444,446 (M⁺).

¹H-NMR (CDCl₃) δ: 2.47(3H,s), 5.01(2H,dd,J=6.71,1.10 Hz),6.48(1H,dt,J=15.75,6.71 Hz), 6.75(1H,d,J=15.75 Hz), 6.93(1H,s),7.00-7.14(6H,m), 7.20-7.33(5H,m), 7.34-7.42(2H,m).

IR (KBr) cm⁻¹: 1665,1598,1582,1493,1095,967,948.

Example 57 Preparation of5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2-(3-phenylpropyl)-2H-pyridazin-3-one

Using 5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 51 were repeatedlikewise, whereby the title compound was obtained in a yield of 97.5%.

Pale yellow oil.

Mass (m/e): 446,448 (M⁺).

¹H-NMR (CDCl₃) δ: 2.23(2H,q,J=7.48 Hz), 2.47(3H,s), 2.76(2H,t,J=7.48Hz), 4.32(2H,t,J=7.48 Hz), 6.87(1H,s), 7.02-7.31(13H,m).

IR (KBr) cm⁻¹: 1665,1598,1582,1493,1095,967,948.

Example 58 Preparation of5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2-cyclopropylmethyl-2H-pyridazin-3-one

Using 5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 51 were repeatedlikewise, whereby the title compound was obtained in a yield of 99.7%.

Yellow amorphous.

¹H-NMR (CDCl₃) δ: 0.48-0.60(4H,m), 1.43-1.49(1H,m), 2.73(3H,s),4.14(2H,d,J=7.32 Hz), 6.92(1H,s), 7.01(2H,t,J=8.54 Hz), 7.09-7.12(2H,m),7.36(2H,d,J=8.05 Hz), 7.56(2H,d,J=8.29 Hz).

IR (KBr) cm⁻¹: 1664,1599,1578,1510,1229,1093,840.

Example 59 Preparation of5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2-cyclopentylmethyl-2H-pyridazin-3-one

Using 5-(4-fluorophenyl)-6-(4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 58 were repeatedlikewise, whereby the title compound was obtained in a yield of 76.6%.

Colorless amorphous.

Mass (m/e): 394 (M⁺).

¹H-NMR (CDCl₃) δ: 1.36-1.45(2H,m), 1.54-1.60(2H,m), 1.66-1.80(4H,m),2.46(3H,s), 2.53-2.64(1H,m), 4.21(2H,d,J=7.56 Hz), 6.90(1H,s),7.00(2H,t,J=8.54 Hz), 7.07-7.13(6H,m).

IR (KBr) cm⁻¹: 1669,1598,1578,1510,1228,1160,1096,840, 680.

Example 60 Preparation of5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2-(2,2,2-trifluoroethyl)-2H-pyridazin-3-one

Using 5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 58 were repeatedlikewise, whereby the title compound was obtained in a yield of 72.3%.

Colorless amorphous.

Mass (m/e): 394,395 (M⁺).

¹H-NMR (CDCl₃) δ: 2.47(3H,s), 4.88(2H,q,J=8.40 Hz), 6.95(1H,s),6.99-7.14(8H,m).

IR (KBr) cm⁻¹: 1678,1597,1513,1335,1263,1088,843,827.

Example 61 Preparation of5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2-benzyl-2H-pyridazin-3-one

Using 5-(4-fluorophenyl)-6-(4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 58 were repeatedlikewise, whereby the title compound was obtained in a yield of 82.0%.

Colorless needles (ethyl acetate-hexane).

Melting point: 140.6-140.7° C.

Mass (m/e): 402 (M⁺).

¹H-NMR (CDCl₃) δ: 2.46(3H,s), 5.42(2H,s), 6.90(1H,s), 6.95-7.12(8H,m),7.31-7.39(3H,m), 7.52-7.55(2H,m).

IR (KBr) cm⁻¹: 1664,1601,1509,1232,1098,841,699.

Example 62 Preparation of5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2-(4-methoxybenzyl)-2H-pyridazin-3-one

Using 5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 58 were repeatedlikewise, whereby the title compound was obtained in a yield of 96.2%.

Colorless needles (ethyl acetate-hexane).

Melting point: 165.3-165.7° C.

Mass (m/e): 432 (M⁺).

¹H-NMR (CDCl₃) δ: 2.46(3H,s), 3.80(3H,s), 5.35(2H,s), 6.87(1H,s),6.88(2H,d,J=6.83 Hz), 6.98(2H,t,J=8.66 Hz), 7.01-7.16(6H,m),7.50(2H,d,J=8.78 Hz).

IR (KBr) cm⁻¹: 1663,1511,1246,1233,842.

Example 63 Preparation of5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2-[4-(methylthio)benzyl]-2H-pyridazin-3-one

Using 5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 58 were repeatedlikewise, whereby the title compound was obtained in a yield of 80.3%.

Colorless plate crystals (ethyl acetate-hexane).

Melting point: 116.0-116.1° C.

Mass (m/e): 448 (M⁺).

¹H-NMR (CDCl₃) δ: 2.47(6H,s), 5.36(2H,s), 6.89(1H,s), 6.99(2H,t,J=8.69Hz), 7.04-7.12(6H,m), 7.24(2H,d,J=8.40 Hz), 7.47(2H,d,J=8.40 Hz).

IR (KBr) cm⁻¹: 1660,1599,1576,1511,1495,1233,1161,1093, 950,841,678.

Example 64 Preparation of5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl)-2-(4-fluorobenzyl)-2H-pyridazin-3-one

Using 5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 58 were repeatedlikewise, whereby the title compound was obtained in a yield of 89.8%.

Colorless needles (ethyl acetate-hexane).

Melting point: 155.9-156.2° C.

Mass (m/e): 448,449 (M⁺).

¹H-NMR (CDCl₃) δ: 2.46(3H,s), 5.37(2H,s), 6.89(1H,s), 6.95-7.13(9H,m),7.30-7.35(1H,m), 7.52(2H,dd,J=8.54,5.37 Hz).

IR (KBr) cm⁻¹: 1664,1602,1510,1225,847,812.

Example 65 Preparation of5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2-(2,4-dichlorobenzyl)-2H-pyridazin-3-one

Using 5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 58 were repeatedlikewise, whereby the title compound was obtained in a yield of 61.7%.

Colorless needles (ethyl acetate-hexane).

Melting point: 139.3-139.5° C.

Mass (m/e): 470,472 (M⁺).

¹H-NMR (CDCl₃) δ: 2.44(3H,s), 5.51(2H,s), 6.94(1H,s), 6.97-7.43(11H,m).

IR (KBr) cm⁻¹: 1665,1583,1510,1233,1098,828.

Example 66 Preparation of5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2-(2,4-difluorobenzyl)-2H-pyridazin-3-one

Using 5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 58 were repeatedlikewise, whereby the title compound was obtained in a yield of 21.0%.

Colorless oil.

¹H-NMR (CDCl₃) δ: 2.46(3H,s), 5.45(2H,s), 6.78-6.88(2H,m), 6.91(1H,s),6.98-7.12(8H,m), 7.37-7.49(1H,m).

IR (KBr) cm⁻¹: 1652,1605,1575,1507,1235,1091,972,842.

Example 67 Preparation of5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2-(3-pyridylmethyl)-2H-pyridazin-3-one

Using 5-(4-fluorophenyl)-6-(4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 58 were repeatedlikewise, whereby the title compound was obtained in a yield of 31.7%.

Colorless needles (acetone-water).

Melting point: 159.8-160.7° C.

Mass (m/e): 403 (M⁺).

¹H-NMR (CDCl₃) δ: 2.46(3H,s), 5.43(2H,s), 6.91(1H,s), 6.96-7.13(8H,m),7.30(1H,dd,J=8.30,5.37 Hz), 7.89(1H,dt,J=7.80,1.96 Hz),8.58(1H,dd,J=4.77,1.51 Hz), 8.79(1H,d,J=1.71 Hz).

IR (KBr) cm⁻¹: 1661,1580,1509,1216,1095,955,852,832, 680.

Example 68 Preparation of5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2-(4-pyridylmethyl)-2H-pyridazin-3-one

Using 5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 58 were repeatedlikewise, whereby the title compound was obtained in a yield of 23.5%.

Colorless crystals.

Melting point: 223.4-224.3%

Mass (m/e): 403 (M⁺).

¹H-NMR (DMSO-D₆) δ: 2.44(3H,s), 5.39(2H,s), 7.04(1H,s), 7.08(2H,d,J=8.29Hz), 7.16(2H,d,J=8.54 Hz), 7.19-7.29(4H,m), 7.34(2H,d,J=5.61 Hz),8.35(2H,d,J=5.85 Hz).

IR (KBr) cm⁻¹: 1664,1601,1582,1562,1510,1417,1219,852, 683.

Example 69 Preparation of5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl)-2-(2,4-difluorocinnamyl)-2H-pyridazin-3-one

Using 5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 58 were repeatedlikewise, whereby the title compound was obtained in a yield of 49.5%.

Colorless amorphous.

Mass (m/e): 464 (M⁺).

¹H-NMR (CDCl₃) δ: 2.46(3H,s), 5.02(2H,d,J=6.34 Hz),6.48(1H,dt,J=16.11,6.59 Hz), 6.74-6.85(3H,m), 6.93(1H,s),6.97-7.14(8H,m), 7.39-7.45(1H,m).

IR (KBr) cm⁻¹: 1664,1554,1502,1273,1232,1094,966,841.

Example 70 Preparation of2-(4-chlorocinnamyl)-5-(4-fluoro-phenyl)-6-[4-(methylthio)phenyl)-2H-pyridazin-3-one

Using 5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 58 were repeatedlikewise, whereby the title compound was obtained in a yield of 67.5%.

Colorless needles (ethyl acetate-hexane).

Melting point: 118.6-118.9° C.

¹H-NMR (CDCl₃) δ: 2.46(3H,s), 5.00(2H,d,J=5.62 Hz),6.44(1H,dt,J=15.87,6.59 Hz), 6.70(1H,d,J=16.12 Hz), 6.93(1H,s),6.97-7.13(8H,m), 7.26(2H,d,J=5.79 Hz), 7.33(2H,d,J=8.55 Hz).

IR (KBr) cm⁻¹: 1669,1605,1575,1509,1492,1095,841,830.

Example 71 Preparation of2-benzyl-6-[4-(methylthio)phenyl]-5-phenyl-2H-pyridazin-3-one

Using 6-(4-(methylthio)phenyl]-5-phenyl-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 51 were repeated likewise, wherebythe title compound was obtained in a yield of 55.3%.

Colorless needles (ethyl acetate).

Melting point: 157.3-158.4° C.

Mass (m/e): 384,386 (M⁺).

¹H-NMR (CDCl₃) δ: 2.45(3H,s), 5.43(2H,s), 6.92(1H,s), 7.05-7.12(6H,m),7.25-7.40(6H,m), 7.51-7.57(2H,m).

IR (KBr) cm⁻¹: 1665,1597,1585,1493,775,711.

Example 72 Preparation of2-acetonyl-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one as a startingmaterial, propargyl chloride was treated in a similar manner as inExample 12, whereby the title compound was obtained in a yield of 29.3%.

Colorless crystalline powder (diethyl ether-hexane).

Melting point: 68.3-70.6° C.

¹H-NMR (CDCl₃) δ: 2.30(3H,s), 3.78(3H,s), 5.07(2H,s), 6.77(2H,d,J=8.54Hz), 6.98(1H,s), 7.04-7.10(4H,m), 8.58(2H,td,J=0.85,4.39 Hz).

IR (KBr) cm⁻¹: 1734,1669,1610,1517,1250,1170.

Example 73 Preparation of2-cyclopropylmethyl-6-(4-methoxy-phenyl)-5-(4-pyridyl)-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 72 were repeated likewise, wherebythe title compound was obtained in a yield of 70.8%.

Colorless needles (ethyl acetate-hexane).

Melting point: 128.3-130.1° C.

¹H-NMR (CDCl₃) δ: 0.47-0.54(2H,m), 0.55-0.62(2H,m), 1.40-1.52(1H,m),3.79(3H,s), 4.14(2H,d,J=7.08 Hz), 6.79(2H,d,J=8.92 Hz), 6.95(1H,s),7.07(2H,dd,J=1.65,4.91 Hz), 7.09(2H,d,J=8.92 Hz), 8.58(2H,dd,J=1.65,4.91Hz).

IR (KBr) cm¹: 1664,1610,1582,1572,1517,1254,1024,834.

Example 74 Preparation of2-cyclopentylmethyl-6-(4-methoxy-phenyl)-5-(4-pyridyl)-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 72 were repeated likewise, wherebythe title compound was obtained in a yield of 32.0%.

Colorless prisms (methylene chloride-hexane).

Melting point: 119.3-120.2° C.

¹H-NMR (CDCl₃) δ: 1.33-1.49(2H,m), 1.52-1.64(2H,m), 1.65-1.84(4H,m),2.59(1H,septet,J=7.61 Hz), 3.79(3H,s), 4.22(2H,d,J=7.61 Hz),6.79(2H,d,J=8.85 Hz), 6.94(1H,s), 7.07(2H,dd,J=1.71,4.44 Hz),7.09(2H,d,J=8.88 Hz), 8.57(2H,dd,J=1.71,4.44 Hz).

IR (KBr) cm⁻¹: 1668,1610,1601,1572,1517,1250,1180,827.

Example 75 Preparation of2-benzyl-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 72 were repeated likewise, wherebythe title compound was obtained in a yield of 43.1%.

Pale yellow needles (ethyl acetate-hexane).

Melting point: 153.9-155.1° C.

¹H-NMR (CDCl₃) δ: 3.78(3H,s), 5.42(2H,s), 6.78(2H,d,J=8.66 Hz),6.93(1H,s), 7.03(2H,d,J=5.73 Hz), 7.06(2H,d,J=8.66 Hz), 7.35-7.39(3H,m),7.54(2H,d,J=7.07 Hz), 8.56(2H,d,J=5.73 Hz).

IR (KBr) cm¹: 1668,1601,1517,1251,1182,826,761.

Example 76 Preparation of2-(4-methoxybenzyl)-6-(4-methoxy-phenyl)-5-(4-pyridyl)-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 72 were repeated likewise, wherebythe title compound was obtained in a yield of 37.2%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 142.6-143.3° C.

¹H-NMR (CDCl₃) δ: 3.78(6H,s), 5.36(2H,s), 6.78(2H,d,J=8.66 Hz),6.88(2H,d,J=8.42 Hz), 6.92(1H,d,J=1.46 Hz), 7.02(2H,d,J=4.64 Hz),7.07(2H,d,J=8.66 Hz), 7.50(2H,d,J=8.42 Hz), 8.56(2H,d,J=3.64 Hz).

IR (KBr) cm⁻¹: 1665,1609,1598,1570,1514,1296,1250,1179, 1025,844,829.

Example 77 Preparation of2-(4-fluorobenzyl)-6-(4-methoxy-phenyl)-5-(4-pyridyl)-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 72 were repeated likewise, wherebythe title compound was obtained in a yield of 42.2%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 154.3-155.2° C.

¹H-NMR (CDCl₃) δ: 3.78(3H,s), 5.38(2H,s), 6.79(2H,d,J=8.78 Hz),6.93(1H,s), 6.98-7.04(4H,m)), 7.07(2H,d,J=8.78 Hz),7.53(2H,dd.J=8.54,5.61 Hz), 7.56(2H,d,J=5.86 Hz).

IR (KBr) cm⁻¹: 1666,1609,1601,1572,1517,1509,1297,1253,1226,1182,1158,1028,842,826.

Example 78 Preparation of2-(4-chlorobenzyl)-6-(4-methoxy-phenyl)-5-(4-pyridyl)-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 72 were repeated likewise, wherebythe title compound was obtained in a yield of 81.2%.

Orange prisms (ethyl acetate-hexane).

Melting point: 175.4-176.1° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 5.38(2H,s), 6.79(2H,d,J=8.90 Hz),6.93(1H,s), 7.03(2H,dd,J=1.70,4.37 Hz), 7.05(2H,d,J=8.90 Hz),7.33(2H,d,J=8.42 Hz), 7.48(2H,d,J=8.42 Hz), 8.56(2H,dd,J=1.70,4.37 Hz).

IR (KBr) cm⁻¹: 1665,1608,1598,1571,1517,1492,1252,1181, 843,827.

Example 79 Preparation of2-(2,4-dichlorobenzyl)-6-(4-methoxy-phenyl)-5-(4-pyridyl)-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 72 were repeated likewise, wherebythe title compound was obtained in a yield of 47.2%.

Pale yellowish-brown prisms (methanol-diethyl ether).

Melting point: 151.3-153.0° C.

¹H-NMR (CDCl₃) δ: 3.78(3H,s), 5.53(2H,s), 6.77(2H,d,J=8.79 Hz),6.98(1H,s), 7.04(2H,d,J=8.79 Hz), 7.07(2H,d,J=6.10 Hz),7.22(1H,dd,J=1.96,8.31 Hz), 7.29(2H,d,J=8.31 Hz), 7.44(1H,d,J=1.96 Hz),8.59(2H,d,J=6.10 Hz).

IR (KBr) cm⁻¹: 1658,1610,1596,1517,1490,1250,1185.

Example 80 Preparation of6-(4-methoxyphenyl)-5-(4-pyridyl)-2-(3-pyridylmethyl)-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 72 were repeated likewise, wherebythe title compound was obtained in a yield of 55.1%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 161.7-162.3° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 5.44(2H,s), 6.79(2H,d,J=8.78 Hz),6.95(1H,s), 7.04(2H,dd,J=1.71,4.39 Hz), 7.06(2H,d,J=8.78 Hz),7.31(1H,ddd,J=0.73,4.88,7.81 Hz), 7.91(1H,td,J=1.95,7.81 Hz),8.56-8.60(3H,m), 8.81(1H,d,J=1.95 Hz).

IR (KBr) cm⁻¹: 1665,1610,1599,1587,1574,1518,1264,1252,1181,1023,839,829,716.

Example 81 Preparation of6-(4-methoxyphenyl)-5-(4-pyridyl)-2-(4-pyridylmethyl)-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 72 were repeated likewise, wherebythe title compound was obtained in a yield of 45.4%.

Colorless prisms (chloroform-hexane).

Melting point: 192.8-194.4° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 5.42(2H,s), 6.79(2H,d,J=8.90 Hz),6.98(1H,s), 7.06(2H,dd,J=1.71,4.39 Hz), 7.06(2H,d,J=8.90 Hz),7.38(2H,dd,J=1.71,4.39 Hz), 8.58(2H,dd,J=1.71,4.39 Hz),8.60(2H,dd,J=1.71,4.39 Hz).

IR (KBr) cm⁻¹: 1665,1602,1585,1516,1417,1301,1250,1174, 838,720.

Example 82 Preparation of2-cinnamyl-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 72 were repeated likewise, wherebythe title compound was obtained in a yield of 29.9%.

Pale yellow amorphous.

¹H-NMR (CDCl₃) δ: 3.79(3H,s),

5.02(2H,dd,J=0.98,6.59 Hz), 6.47(1H,td,J=6.59,15.86 Hz),6.77(1H,dd,J=0.98,15.86 Hz), 6.79(2H,d,J=8.79 Hz), 6.96(1H,s),7.05(2H,d,J=6.11 Hz), 7.09(2H,d,J=8.79 Hz), 7.21-7.31(3H,m),7.33-7.40(2H,m), 8.57(2H,d,J=6.11 Hz).

IR (KBr) cm⁻¹: 1668,1609,1516,1485,1482,1251,1178.

Example 83 Preparation of6-(4-methoxyphenyl)-5-(4-pyridyl)-2-(3-phenylpropyl)-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 72 were repeated likewise, wherebythe title compound was obtained in a yield of 70.7%.

Reddish brown prisms (ethyl acetate-diethyl ether-hexane).

Melting point: 67.7-68.3° C.

¹H-NMR (CDCl₃) δ: 2.26(2H,quintet,J=7.33 Hz), 2.77(2H,t,J=7.33 Hz),3.79(3H,s), 4.33(2H,t,J=7.33 Hz), 6.79(2H,d,J=8.79 Hz), 6.90(1H,s),7.01(2H,d,J=6.11 Hz), 7.06(2H,d,J=8.79 Hz), 7.15-7.30(5H,m),8.57(2H,d,J=6.11 Hz).

IR (KBr) cm⁻¹: 1665,1608,1517,1496,1298,1252,1181.

Example 84 Preparation of2-(2,4-difluorocinnamyl)-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 72 were repeated likewise, wherebythe title compound was obtained in a yield of 30.7%.

Colorless crystalline powder (ethyl acetate-diethyl ether).

Melting point: 55.4-56.9° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 5.03(2H,d,J=6.59 Hz),6.49(1H,td,J=6.59,16.03 Hz), 6.73-6.88(5H,m), 6.98(1H,s),7.02-7.15(4H,m), 7.43(1H,dd,J=8.67,15.02 Hz), 8.58(2H,brs).

IR (KBr) cm⁻¹: 1668,1610,1516,1502,1297,1251,1178,965, 829.

Example 85 Preparation of2-benzyl-5-(4-chlorophenyl)-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

2-Benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one (100 mg, 0.239 mmol) wasdissolved in dichloromethane (5 ml). Under cooling at −20° C.,methachloroperbenzoic acid (60%) (68.7 mg, 0.239 mmol) was added. Theresulting mixture was stirred through the night until its temperaturearose to room temperature. A saturated aqueous solution of sodiumhydrogencarbonate was added. After the resulting mixture was extractedwith chloroform, the extract was washed with water and then dried overanhydrous sodium sulfate. The solvent was distilled off, and the residueso obtained was then separated and purified by silica gel preparativechromatography [hexane/ethyl acetate (½)], whereby the title compound(91.8 mg, 88.4%) was obtained.

Colorless crystalline powder (hexane-diethyl ether)

Melting point: 143.7-144.7° C.

Mass (m/e): 434,436 (M⁺).

¹H-NMR (CDCl₃) δ: 2.72(3H,s), 5.43(2H,s), 6.94(1H,s), 7.02(2H,d,J=8.59Hz), 7.27(2H,d,J=8.30 Hz), 7.29-7.40(5H,m), 7.49-7.52(2H,m),7.55(2H,d,J=8.54 Hz).

IR (KBr) cm⁻¹: 1665,1583,1494,1091,1050,1015,951,833.

Example 86 Preparation of5-(4-chlorophenyl)-2-cyclopropyl-methyl-6-[4-(methylsulfinyl)phenyl-2H-pyridazin-3-one

Using5-(4-chlorophenyl)-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 85 were repeatedlikewise, whereby the title compound was obtained in a yield of 77.0%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 152.2-152.3° C.

Mass (m/e): 398,400 (M⁺).

¹H-NMR (CDCl₃) δ: 0.48-0.62(4H,m), 1.42-1.49(1H,m), 2.73(3H,s),4.14(2H,d,J=7.42 Hz), 6.95(1H,s), 7.05(2H,d,J=8.40 Hz), 7.29(2H,d,J=8.40Hz), 7.36(2H,d,J=8.40 Hz), 7.56(2H,d,J=8.40 Hz).

IR (KBr) cm⁻¹: 1661,1584,1494,1317,1090,1051,838.

Example 87 Preparation of2-cyclopropylmethyl-5-(4-fluoro-phenyl)-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Using2-cyclopropylmethyl-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 85 were repeatedlikewise, whereby the title compound was obtained in a yield of 72.1%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 133.3-133.5° C.

Mass (m/e): 382 (M⁺).

¹H-NMR (CDCl₃) δ: 0.49-0.62(4H,m), 1.42-1.48(1H,m), 3.05(3H,s),4.14(2H,d,J=7.42 Hz), 6.96(1H,s), 7.03(2H,t,J=8.50 Hz), 7.08-7.11(2H,m),7.40(2H,d,J=8.40 Hz), 7.85(2H,d,J=8.20 Hz).

IR (KBr) cm⁻¹: 1664,1582,1511,1220,1055,840,612.

Example 88 Preparation of2-benzyl-5-(4-fluorophenyl)-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Using2-benzyl-5-(4-fluorophenyl)-6-(4-(methylthio)phenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 85 were repeatedlikewise, whereby the title compound was obtained in a yield of 24.2%.

Colorless needles (ethyl acetate-hexane).

Melting point: 197.7-198.2° C.

¹H-NMR (CDCl₃) δ: 2.72(3H,s), 5.44(2H,s), 6.99(1H,s), 6.97-7.07(4H,m),7.31-7.39(5H,m), 7.52-7.56(4H,m).

IR (KBr) cm⁻¹: 1665,1511,1231,1049,954,840.

Example 89 Preparation of5-(4-fluorophenyl)-2-(4-methoxy-benzyl)-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Using5-(4-fluorophenyl)-2-(4-methoxybenzyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 85 were repeatedlikewise, whereby the title compound was obtained in a yield of 94.3%.

Colorless powder (ethyl acetate-hexane).

Melting point: 81.3-81.5° C.

Mass (m/e): 448 (M⁺).

¹H-NMR (CDCl₃) δ: 2.73(3H,s), 3.79(3H,s), 5.37(2H,s), 6.89(2H,d,J=8.54Hz), 6.92(1H,s), 6.99(2H,t,J=8.66 Hz), 7.03-7.07(2H,m), 7.33(2H,d,J=8.54Hz), 7.50(2H,d,J=8.78 Hz), 7.55(2H,d,J=8.54 Hz).

IR (KBr) cm⁻¹: 1664,1512,1248,1047,840.

Example 90 Preparation of2-(4-fluorobenzyl)-5-(4-fluoro-phenyl)-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Using2-(4-fluorobenzyl)-5-(4-fluorophenyl)-6-(4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 85 were repeatedlikewise, whereby the title compound was obtained in a yield of 80.6%.

Colorless needles (ethyl acetate-hexane).

Melting point: 198.1-198.3° C.

¹H-NMR (CDCl₃) δ: 2.73(3H,s), 5.39(2H,s), 6.94(1H,s), 6.94-7.08(6H,m),7.32(2H,d,J=8.06 Hz), 7.50-7.57(2H, m)

IR (KBr) cm⁻¹: 1665,1511,1225,1157,1051,850,842.

Example 91 Preparation of2-(2,4-difluorobenzyl)-5-(4-chloro-phenyl)-6-[4-(methylsulfinyl)phenyl)-2H-pyridazin-3-one

Using2-(2,4-difluorobenzyl)-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 85 were repeatedlikewise, whereby the title compound was obtained in a yield of 81.1%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 155.6-155.7° C.

Mass (m/e): 470,472 (M⁺)

¹H-NMR (CDCl₃) δ: 2.72(3H,s), 5.46(2H,s), 6.83-6.90(2H,m), 6.95(1H,s),7.03(2H,d,J=8.59 Hz), 7.29(2H,d,J=8.40 Hz), 7.31(2H,d,J=8.20 Hz),7.50-7.52(1H,m), 7.55(2H,d,J=8.20 Hz).

IR (KBr) cm⁻¹: 1667,1604,1506,1272,1052,971,951,838.

Example 92 Preparation of5-(4-chlorophenyl)-2-(2,4-dichloro-benzyl)-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Using5-(4-chlorophenyl)-2-(2,4-dichlorobenzyl)-6-[4-(methylthio)phenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 85 were repeatedlikewise, whereby the title compound was obtained in a yield of 71.6%.

Colorless needles (chloroform-hexane).

Melting point: 236.5-237.3° C.

Mass (m/e): 502,504 (M⁺).

¹H-NMR (CDCl₃) δ: 2.72(3H,s), 5.53(2H,s), 6.98(1H,s), 7.05(2H,d,J=8.55Hz), 7.24(1H,dd,J=8.30,2.03 Hz), 7.27-7.34(5H,m), 7.45(1H,d,J=8.03 Hz),7.54(2H,d,J=8.79 Hz).

IR (KBr) cm⁻¹: 1665,1588,1492,1473,1091,1051,1016,954, 835.

Example 93 Preparation of2-(2,4-dichlorobenzyl)-5-(4-fluoro-phenyl)-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Using2-(2,4-dichlorobenzyl)-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 85 were repeatedlikewise, whereby the title compound was obtained in a yield of 86.5%.

Colorless needles (ethyl acetate-hexane).

Melting point: 214.4-214.5° C.

¹H-NMR (CDCl₃) δ: 2.71(3H,s), 5.53(2H,s), 6.98(1H,s), 6.99-7.12(4H,m),7.22-7.31(4H,m), 7.44(1H,d,J=1.95 Hz), 7.54(2H,d,J=8.05 Hz).

IR (KBr) cm⁻¹: 1668,1510,1235,1047,840,609.

Example 94 Preparation of5-(4-chlorophenyl)-6-[4-(methyl-sulfinyl)phenyl]-2-(3-pyridylmethyl)-2H-pyridazin-3-one

Using5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2-(3-pyridylmethyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 85 were repeatedlikewise, whereby the title compound was obtained in a yield of 98.5%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 154.6-154.7° C.

Mass (m/e): 435,437 (M⁺).

¹H-NMR (CDCl₃) δ: 2.74(3H,s), 5.45(2H,s), 6.96(1H,s), 7.03(2H,d,J=8.59Hz), 7.23-7.34(5H,m), 7.57(2H,d,J=8.40 Hz), 7.89(1H,tt,J=7.81,1.95 Hz),8.58(1H,dd,J=4.88,1.66 Hz), 8.79(1H,d,J=1.56 Hz).

IR (KBr) cm⁻¹: 1664,1584,1494,1090,1050,837.

Example 95 Preparation of5-(4-fluorophenyl)-6-(4-(methyl-sulfinyl)phenyl]-2-(4-pyridylmethyl)-2H-pyridazin-3-one

Using5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2-(4-pyridylmethyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 85 were repeatedlikewise, whereby the title compound was obtained. The title compoundwas then converted into its methanesulfonate (yield: 88.1%).

Colorless needles (methanol-diethyl ether).

Melting point: 212.8-218.5° C. (decomposed)

¹H-NMR (CDCl₃-CD₃OD) δ: 2.45(3H,s), 2.69(3H,s), 5.73(2H,s), 7.06(1H,s),7.08(2H,d,J=8.77 Hz), 7.14(4H,s), 7.25(2H,dd,J=8.79,5.12 Hz),8.05(2H,d,J=6.10 Hz), 8.82(2H,d,J=6.83 Hz).

IR (KBr) cm⁻¹: 1664,1601,1510,1210,1192,1050,843.

Example 96 Preparation of2-(2,4-difluorocinnamyl)-5-(4-fluoro-phenyl)-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Using2-(2,4-difluorocinnamyl)-5-(4-fluoro-phenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 85 were repeatedlikewise, whereby the title compound was obtained in a yield of 58.1%.

Colorless amorphous.

¹H-NMR (CDCl₃-CD₃OD) δ: 2.72(3H,s), 5.03(2H,d,J=6.59 Hz),6.49(1H,dt,J=15.87,6.65 Hz), 6.77-6.85(3H,m), 6.96(1H,s),6.99-7.10(4H,m) 7.35(2H,d,J=8.30 Hz), 7.44(1H,dd,J=15.01,8.42 Hz),7.56(2H,d,J=8.06 Hz).

IR (KBr) cm⁻¹: 1665,1502,1274,1230,1050,966,841.

Example 97 Preparation of2-benzyl-5-(4-chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

2-Benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one(159.2 mg, 0.380 mmol) and sodium periodate (325.2 mg, 1.402 mmol) weredissolved in a mixed solvent of acetone (40 ml)-water (20 ml)-chloroform(5 ml). Under ice cooling, osmium tetraoxide/tert-butanol (1 g/25 ml)(0.24 ml) was added, and the mixture was stirred through the night untilits temperature arose to room temperature. The reaction mixture wasconcentrated, and the residue was extracted with chloroform. The extractwas dried over anhydrous sodium sulfate and then concentrated. Theresidue was separated and purified by silica gel preparativechromatography [hexane/ethyl acetate (1/1)], whereby the title compound(151.1 mg, 88.2%) was obtained.

Colorless crystalline powder (ethyl acetate-hexane)

Melting point: 103.2-105.7° C.

Mass (m/e): 450,452 (M⁺).

¹H-NMR (CDCl₃-CD₃OD) δ: 3.06(3H,s), 5.43(2H,s), 6.95(1H,s),7.01(2H,d,J=8.59 Hz), 7.30(2H,d,J=8.59 Hz), 7.33-7.41(5H,m),7.49-7.55(2H,m), 7.84(2H,d,J=8.79 Hz).

IR (KBr) cm⁻¹: 1668,1316,1153,1091,951.

Example 98 Preparation of5-(4-chlorophenyl)-6-[4-(methyl-sulfonyl)phenyl]-2H-pyridazin-3-one

Using 5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 97 were repeatedlikewise, whereby the title compound was obtained in a yield of 60.9%.

Colorless prisms (methylene chloride-methanol-hexane).

Melting point: 254.0-254.7° C.

Mass (m/e): 360,362 (M⁺).

¹H-NMR (CDCl₃) δ: 3.07(3H,s), 7.02(1H,s), 7.06(2H,d,J=8.55 Hz),7.33(2H,d,J=8.55 Hz), 7.42(2H,d,J=8.55 Hz), 7.86(2H,d,J=8.55 Hz),12.40(1H,brs).

IR (KBr) cm⁻¹: 1661,1587,1316,1153,1095.

Example 99 Preparation of5-(4-chlorophenyl)-2-cyclopropylmethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Using5-(4-chlorophenyl)-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 97 were repeatedlikewise, whereby the title compound was obtained in a yield of 20.6%.

Colorless needles (ethyl acetate-hexane).

Melting point: 139.7-139.8° C.

Mass (m/e): 414,416 (M⁺).

¹H-NMR (CDCl₃) δ: 0.49-0.63(4H,m), 1.41-1.49(1H,m), 3.06(3H,s),4.14(2H,d,J=7.22 Hz), 6.96(1H,s), 7.05(2H,d,J=8.59 Hz), 7.31(2H,d,J=8.59Hz), 7.41(2H,d,J=8.59 Hz), 7.86(2H,d,J=8.59 Hz).

IR (KBr) cm⁻¹: 1664,1584,1313,1303,1151.

Example 100 Preparation of2-cyclopropylmethyl-5-(4-fluoro-phenyl)-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Using2-cyclopropylmethyl-5-(4-fluorophenyl)-6-(4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 97 were repeatedlikewise, whereby the title compound was obtained in a yield of 87.1%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 123.8-123.9° C.

Mass (m/e): 398 (M⁺).

¹H-NMR (CDCl₃) δ: 0.48-0.63(4H,m), 1.42-1.48(1H,m), 3.05(3H,s),4.14(2H,d,J=7.42 Hz), 6.96(1H,s), 7.03(2H,t,J=8.50 Hz), 7.08-7.11(2H,m),7.40(2H,d,J=8.40 Hz), 7.85(2H,d,J=8.20 Hz).

IR (KBr) cm⁻¹: 1664,1511,1316,1229,1153,954,852,613.

Example 101 Preparation of2-benzyl-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Using2-benzyl-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 97 were repeatedlikewise, whereby the title compound was obtained in a yield of 99.0%.

Pale yellow needles (ethyl acetate-hexane).

Melting point: 187.6-188.0° C.

¹H-NMR (CDCl₃) δ: 3.05(3H,s), 5.43(2H,s), 6.95(1H,s), 7.01-7.07(4H,m),7.33-7.40(5H,m), 7.53(2H,dd,J=7.69,1.83 Hz), 7.84(2H,d,J=8.55 Hz).

IR (KBr) cm⁻¹: 1668,1595,1582,1510,1313,1154,955,849, 779.

Example 102 Preparation of5-(4-fluorophenyl)-2-(4-methoxy-benzyl)-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Using5-(4-fluorophenyl)-2-(4-methoxybenzyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 97 were repeatedlikewise, whereby the title compound was obtained in a yield of 99.0%.

Colorless amorphous.

Mass (m/e): 464 (M⁺).

¹H-NMR (CDCl₃) δ: 3.05(3H,s), 3.80(3H,s), 5.37(2H,s), 6.89(2H,d,J=8.01Hz), 6.93(1H,s), 7.01-7.05(4H,m), 7.36(2H,d,J=8.20 Hz), 7.48(2H,d,J=8.01Hz), 7.83(2H,d,J=8.01 Hz).

IR (KBr) cm⁻¹: 1668,1512,1315,1248,1153,842.

Example 103 Preparation of2-(2,4-difluorobenzyl)-5-(4-chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Using2-(2,4-difluorobenzyl)-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 97 were repeatedlikewise, whereby the title compound was obtained in a yield of 94.5%.

Colorless needles (ethyl acetate-hexane).

Melting point: 173.8-173.9° C.

Mass (m/e): 486,488 (M⁺).

¹H-NMR (CDCl₃) δ: 3.05(3H,s), 5.46(2H,s), 6.83-6.90(2H,m), 6.96(1H,s),7.03(2H,d,J=8.40 Hz), 7.31(2H,d,J=8.40 Hz), 7.35(2H,d,J=8.20 Hz),7.48-7.54(1H,m), 7.84(2H,d,J=8.20 Hz).

IR (KBr) cm⁻¹: 1668,1507,1316,1153,1093,972,837.

Example 104 Preparation of5-(4-chlorophenyl)-2-(2,4-dichloro-benzyl)-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Using5-(4-chlorophenyl)-2-(2,4-dichlorobenzyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 97 were repeatedlikewise, whereby the title compound was obtained in a yield of 53.3%.

Colorless scales (chloroform-hexane).

Melting point: 232.7-234.5° C.

Mass (m/e): 518,520 (M⁺).

¹H-NMR (CDCl₃) δ: 3.05(3H,s), 5.54(2H,s), 6.99(1H,s), 7.03(2H,d,J=8.30Hz), 7.25(1H,dd,J=8.30,2.12 Hz), 7.28-7.40(5H,m), 7.45(1H,d,J=2.12 Hz),7.83(2H,d,J=8.30 Hz).

IR (KBr) cm⁻¹: 1665,1324,1314,1158,1093.

Example 105 Preparation of2-(2,4-dichlorobenzyl)-5-(4-fluoro-phenyl)-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

Using2-(2,4-dichlorobenzyl)-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 97 were repeatedlikewise, whereby the title compound was obtained in a yield of 10.3%.

Colorless needles (ethyl acetate-hexane)

Melting point: 211.8-212.2° C.

¹H-NMR (CDCl₃) δ: 3.04(3H,s), 5.54(2H,s), 6.99(1H,s), 7.01-7.11(4H,m),7.23-7.35(5H,m), 7.45(1H,d,J=2.20 Hz), 7.82(2H,d,J=6.59 Hz).

IR (KBr) cm⁻¹: 1669,1590,1510,1314,1236,1156,954,842, 554.

Example 106 Preparation of5-(4-chlorophenyl)-6-[4-(methyl-sulfonyl)phenyl]-2-(3-pyridylmethyl)-2H-pyridazin-3-one

Using5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2-(3-pyridylmethyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 97 were repeatedlikewise, whereby the title compound was obtained in a yield of 57.5%.

Colorless crystalline powder (ethyl acetate-hexane)

Melting point: 248.0-248.1° C.

Mass (m/e): 451 (M⁺).

¹H-NMR (CDCl₃) δ: 3.08(3H,s), 5.37(2H,s), 6.98(1H,s), 7.03(2H,d,J=8.40Hz), 7.30-7.33(1H,m), 7.32(2H,d,J=8.40 Hz), 7.49(1H,d,J=7.81 Hz),7.86(2H,d,J=8.40 Hz), 8.17(2H,d,J=6.44 Hz), 8.34(1H,s).

IR (KBr) cm⁻¹: 1664,1555,1314,1278,1153,1091.

Example 107 Preparation of5-(4-fluorophenyl)-6-[4-(methyl-sulfonyl)phenyl]-2- (4-pyridylmethyl)-2H-pyridazin-3-one

Using5-(4-fluorophenyl)-6-[4-(methylthio)-phenyl]-2-(4-pyridylmethyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 97 were repeatedlikewise, whereby the title compound was obtained in a yield of 89.1%.

Pale yellow prisms (ethyl acetate-hexane)

Melting point: 253.3-254.5° C.

Mass (m/e): 435 (M⁺).

¹H-NMR (CDCl₃) δ: 3.05(3H,s), 5.42(2H.,d,J=4.15 Hz), 7.00(1H,s),7.03-7.10(4H,m), 7.35-7.38(4H,m), 7.85(2H,d,J=8.30 Hz), 8.61(2H,d,J=5.81Hz).

IR (KBr) cm⁻¹: 1666,1602,1582,1511,1315,1237,1154,944, 848.

Example 108 Preparation of5-(4-chlorophenyl)-6-[4-(methyl-sulfonyl)phenyl]-2-(3-phenylpropyl)-2H-pyridazin-3-one

Using5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2-(3-phenylpropyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 97 were repeatedlikewise, whereby the title compound was obtained in a yield of 72.5%.

Colorless crystalline powder (ethyl acetate-hexane)

Melting point: 70.2-71.6° C.

Mass (m/e): 478,480 (M⁺).

¹H-NMR (CDCl₃) δ: 2.26(2H,q,J=7.45 Hz), 2.77(2H,t,J=7.45 Hz),3.06(3H,s), 4.34(2H,t,J=7.45 Hz), 6.91(1H,s), 7.02(2H,d,J=8.79 Hz),7.14-7.33(7H,m), 7.38(2H,d,J=8.54 Hz), 7.85(2H,d,J=8.54 Hz).

IR (KBr) cm⁻¹: 1664,1584,1494,1314,1152,1091,835,540.

Example 109 Preparation of2-benzyl-6-[4-(methylsulfonyl)-phenyl]-5-phenyl-2H-pyridazin-3-one

Using 2-benzyl-6-[4-(methylthio)phenyl)-5-phenyl-2H-pyridazin-3-one as astarting material, the procedures of Example 97 were repeated likewise,whereby the title compound was obtained in a yield of 72.4%.

Colorless needles (chloroform-hexane)

Melting point: 211.0-212.0° C.

Mass (m/e): 416,418 (M⁺).

¹H-NMR (CDCl₃) δ: 3.04(3H,s), 5.44(2H,s), 6.97(1H,s), 7.04-7.09(2H,m),7.24-7.41(8H,m), 7.50-7.56(2H,m), 7.81(2H,d,J=8.54 Hz).

IR (KBr) cm⁻¹: 1663,1590,1497,1320,1311,1304,1154,957, 779,720,707.

Example 110 Preparation of2-(4-aminobenzyl)-5,6-bis(4-methoxy-phenyl)-2H-pyridazin-3-one

10% palladium on charcoal (200 mg) was added to a solution of5,6-bis(4-methoxyphenyl)-2-(4-nitrobenzyl)-2H-pyridazin-3-one (300 mg,0.68 mmol) in ethyl acetate (30 ml), followed by catalytic reduction atroom temperature and atmospheric pressure. Ninety minutes later, thereaction mixture was filtered. After the catalyst was washed with ethylacetate, the filtrate and the washing were combined. The solvent wasdistilled off, whereby a pale yellow oil (253 mg) was obtained. The oil(253 mg) was separated and purified by silica gel preparativechromatography [developer: chloroform/methanol (20/1)], whereby thetitle compound (250 mg, 89.2%) was obtained as pale yellow amorphous.

¹H-NMR (CDCl₃) δ: 3.70(2H,brs), 3.79(6H,s), 5.29(2H,d,J=8.30 Hz),6.77(2H,d,J=9.03 Hz), 6.79(2H,d,J=8.79 Hz), 6.85(1H,s), 7.00(2H,d,J=9.03Hz), 7.10(2H,d,J=8.79 Hz), 7.37(2H,d,J=8.54 Hz).

Melting point: 171.0-173.0° C. (decomposed)

IR (KBr) cm⁻¹: 3668,3419,2906,2835,1641,1606,1510,1257, 1176,1025,834.

Example 111 Preparation of5,6-bis(4-methoxyphenyl)-2-[4-(dimethylamino)benzyl]-2H-pyridazin-3-oneand5,6-bis(4-methoxyphenyl)-2-[4-(methylamino)benzyl]-2H-pyridazin-3-one

To a solution of2-(4-aminobenzyl)-5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one (245 mg,0.6 mmol) in acetone/N,N-dimethylformamide (5/1) (6 ml), sodiumhydrogencarbonate (378 mg, 4.5 mmol) and a solution of dimethyl sulfatein acetone [an acetone solution of dimethyl sulfate (631 mg) (totalvolume: 5 ml); 3.0 ml, 3.0 mmol)] was added, followed by stirring underheat at 60° C. for 90 minutes. After the acetone was distilled off, theresidue was extracted with ethyl acetate. The organic layer was washedsuccessively with water and a brine, and was then dried over anhydroussodium sulfate. The solvent was distilled off. The pale orange oil (238mg) was separated and purified by silica gel preparative chromatography[developer: chloroform/methanol (20/1)), whereby5,6-bis(4-methoxy-phenyl)-2-[4-(dimethylamino)benzyl]-2H-pyridazin-3-one(80.6 mg, 30.8%) was obtained as a reddish brown oil from fractionshaving large Rf values.

¹H-NMR (CDCl₃) δ: 2.94(6H,s), 3.79(6H,s), 5.32(2H,s), 6.71(2H,d,J=8.79Hz), 6.78(2H,d,J=8.79 Hz), 6.79(2H,d,J=9.03 Hz), 6.85(1H,s),7.07(2H,d,J=8.79 Hz), 7.11(2H,d,J=9.03 Hz), 7.48(2H,d,J=8.79 Hz).

In a manner known per se in the art, the hydrochloride of5,6-bis(4-methoxyphenyl)-2-[4-(dimethylamino)benzyl]-2H-pyridazin-3-onewas obtained in a yield of 67.7%.

Yellow needles (methanol-diethyl ether).

Melting point: 122-126° C.

¹H-NMR (DMSO-D₆+D₂O) δ: 3.06(6H,s), 3.74(3H,s), 3.75(3H,s), 5.33(2H,s),6.86(2H,d,J=8.79 Hz), 6.89(2H,d,J=8.30 Hz), 6.91(1H,s), 7.11(4H,d,J=8.79Hz), 7.30(2H,d,J=8.79 Hz), 7.46(2H,d,J=8.79 Hz).

IR (KBr) cm⁻¹: 3668,3383,1655,1609,1513,1298,1247,1182, 1174,837,827.

From fractions having small Rf values,5,6-bis(4-methoxyphenyl)-2-[4-(methylamino)benzyl]-2H-pyridazin-3-one(47.4 mg, 18.7%) was obtained as a pale brown oil.

¹H-NMR (CDCl₃) δ: 2.82(3H,s), 3.79(6H,s), 5.30(2H,s), 6.58(2H,d,J=8.54Hz), 6.77(2H,d,J=9.03 Hz), 6.79(2H,d,J=8.79 Hz), 6.85(1H,s),7.00(2H,d,J=8.79 Hz), 7.11(2H,d,J=8.78 Hz), 7.42(2H,d,J=8.54 Hz).

IR (film) cm⁻¹: 3410,3373,1652,1610,1515,1296,1249, 1181,1029,833,754.

Example 112 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-carboxybenzyl)-2H-pyridazin-3-one

To a solution of5,6-bis(4-methoxyphenyl)-2-(4-methoxycarbonylbenzyl)-2H-pyridazin-3-one(168 mg, 0.37 mmol) in methanol (4 ml), a 1 N aqueous solution of sodiumhydroxide (1.84 ml) was added, followed by stirring under heat at 40° C.for 4 hours. The methanol was distilled off, and to the residue, a 2 Naqueous solution of hydrochloric acid was added to acidify the residue(pH<1). The thus-acidified mixture was extracted with ethyl acetate. Theorganic layer was washed successively with water and a brine, and wasthen dried over anhydrous sodium sulfate. The solvent was distilled offand the thus-obtained residue (161 mg) was recrystallized fromchloroform-methanol, whereby the title compound (138 mg, 84.7%) wasobtained as colorless needles.

Melting point: 241.0-242.0° C.

Mass (m/e): 442 (M⁺).

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.80(3H,s), 5.48(2H,s), 6.78(2H,d,J=8.79Hz), 6.80(2H,d,J=8.79 Hz), 6.93(1H,s), 7.04(2H,d,J=8.79 Hz),7.10(2H,d,J=8.79 Hz), 7.59(2H,d,J=8.55 Hz), 8.08(2H,d,J=8.30 Hz).

IR (KBr) cm⁻¹: 1706,1632,1611,1553,1254,1180,1025,829.

Example 113 Preparation of5,6-bis(4-methoxyphenyl)-2-[2-(4-methylpiperadinocarbonyl)ethyl]-2H-pyridazin-3-one(1) Preparation of5,6-bis(4-methoxyphenyl)-2-(2-ethoxycarbonylethyl)-2H-pyridazin-3-one

To a solution of 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one (308 mg, 1mmol) in N,N-dimethyl-formamide (3 ml), potassium carbonate (276 mg, 2mmol) and ethyl 3-chloropropionate (273 mg, 2 mmol) were added, followedby stirring at 80° C. for 16 hours. After the reaction mixture wasallowed to cool down, water was added to the reaction mixture and themixture was extracted with ethyl acetate. The organic layer was washedsuccessively with water and a brine, and was then dried over anhydroussodium sulfate. The solvent was distilled off and the residue (416 mg)was separated and purified by chromatography on a silica gel column[silica gel: 11 g, chloroform/ methanol (20/1)], whereby the titlecompound (390 mg, 97%) was obtained as a pale yellow oil.

¹H-NMR (CDCl₃) δ: 1.22(3H,t,J=7.08 Hz), 2.91(2H,t,J=7.32 Hz),3.79(3H,s), 3.81(3H,s), 4.14(2H,q,J=7.08 Hz), 4.55(2H,t,J=7.32 Hz),6.78(2H,d,J=8.79 Hz), 6.81(2H,d,J=8.79 Hz), 6.88(1H,s), 7.04(2H,d,J=8.79Hz), 7.11(2H,d,J=8.79 Hz).

IR (KBr) cm⁻¹: 1733,1659,1607,1515,1297,1250,1179, 1029,845.

(2) Preparation of5,6-bis(4-methoxyphenyl)-2-(2-carboxyethyl)-2H-pyridazin-3-one

A 2 N aqueous solution of sodium hydroxide was added to a solution of5,6-bis(4-methoxyphenyl)-2-(2-ethoxycarbonylethyl)-2H-pyridazin-3-one(390 mg, 0.97 mmol) in methanol (7 ml). The mixture was heated todissolve precipitated crystals, followed by stirring at room temperaturefor 25 hours. After the methanol was distilled off, the residue wasdissolved in water. A 2 N aqueous solution of hydrochloric acid wasadded to the resulting mixture to acidify the same. The mixture wasextracted with ethyl acetate. The organic layer was washed successivelywith water and a brine, and was then dried over anhydrous sodiumsulfate. The solvent was distilled off, and the residue (377 mg) wasseparated and purified by chromatography on a silica gel column (silicagel: 2 g, chloroform/methanol (10/1)], whereby the title compound (356mg, 96.5%) was obtained as a pale yellow amorphous.

Mass (m/e): 380 (M⁺)

¹H-NMR (CDCl₃) δ: 2.97(2H,t,J=7.08 Hz), 3.78(3H,s), 3.80(3H,s),4.57(2H,t,J=7.08 Hz), 6.77(2H,d,J=S8.79 Hz), 6.80(2H,d,J=8.79 Hz),6.93(1H,s) , 7.03(2H,d,J=8.79 Hz), 7.11(2H,d,J=8.79 Hz).

IR (KBr) cm⁻¹: 3427,1637,1609,1511,1297,1249,1178,834.

(3) Preparation of5,6-bis(4-methoxyphenyl)-2-[2-(4-methylpiperadinocarbonyl)ethyl]-2H-pyridazin-3-one

To a solution of5,6-bis(4-methoxyphenyl)-2-(2-carboxyethyl)-2H-pyridazin-3-one (266 mg,0.7 mmol) in tetrahydrofuran (1.3 ml), oxalyl chloride. (133 mg, 1.5 eq)was gradually added dropwise under ice cooling. The mixture was stirredat room temperature for 90 minutes. A solution of triethylamine (283 mg,4.0 eq) and N-methylpiperazine (102 mg, 1.5 eq) in tetrahydrofuran (2ml) was then added, followed by stirring at room temperature for 4hours. The tetrahydrofuran was distilled off and the residue wasextracted with ethyl acetate. The organic layer was washed successivelywith a saturated aqueous solution of sodium hydrogencarbonate, water anda brine, and was then dried over anhydrous sodium sulfate. The solventwas distilled off, and the residue (293 mg) was separated and purifiedby chromatography on a silica gel column [silica gel: 9 g,chloroform/methanol (50/1)], whereby the title compound (272 mg, 84.0%)was obtained as a pale yellow amorphous.

Mass (m/e): 462 (M⁺).

¹H-NMR (CDCl₃) δ: 2.28(3H,s), 2.36-2.38(4H,m), 2.94(2H,t,J=7.81 Hz),3.48-3.52(2H,m), 3.63-3.66(2H,m), 3.79(3H,s), 3.81(3H,s),4.56(2H,t,J=7.81 Hz), 6.78(2H,d,J=9.04 Hz), 6.81(2H,d,J=7.89 Hz),6.88(1H,s), 7.04(2H,d,J=8.79 Hz), 7.12(2H,d,J=8.78 Hz).

IR (KBr) cm⁻¹: 1652,1609,1513,1460,1259,1249,1175,1028, 834.

Example 114 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-methylpiperazinocarbonylmethyl)-2H-pyridazin-3-one

After 5,6-bis(4-methoxyphenyl)-2-carboxymethyl)-2H-pyridazin-3-one (Eur.J. Med. Chem., 14, 53, 1979) was reacted with oxalyl chloride in asimilar manner as in Example 113-(3), a further reaction was conductedwith 4-methylpiperazine, whereby the title compound was obtained in ayield of 20.7%.

Orange amorphous.

¹H-NMR (CDCl₃) δ: 2.30(3H,s), 2.45(4H,m), 3.66-3.71(4H,m), 3.79(3H,s.),3.81(3H,s), 5.32(2H,s), 6.78(2H,d,J=8.79 Hz), 6.82(2H,d,J=8.79 Hz),6.90(1H,s), 7.06(2H,d,J=8.79 Hz), 7.13(2H,d,J=8.79 Hz).

IR (KBr) cm⁻¹: 1659,1609,1513,1463,1294,1259,1176,1028, 834.

Example 115 Preparation of5,6-bis(4-methoxyphenyl)-2-(2-(benzylaminocarbonyl)ethyl]-2H-pyridazin-3-one

After 5,6-bis(4-methoxyphenyl)-2-(2-carboxy-ethyl)-2H-pyridazin-3-onewas reacted with oxalyl chloride in a similar manner as in Example113-(3), a further reaction was conducted with benzylamine, whereby thetitle compound was obtained in a yield of 52.2%.

Colorless fine needles (ethyl acetate-hexane).

Melting point: 135.0-137.0° C.

Mass (m/e): 469 (M⁺).

¹H-NMR (CDCl₃) δ: 2.88(2H,t,J=6.83 Hz), 3.79(3H,s), 3.81(3H,s),4.43(2H,d,J=5.85 Hz), 4.57(2H,t,J=6.83 Hz), 6.71(1H,m), 6.76(2H,d,J=8.79Hz), 6.81(2H,d,J=8.79 Hz), 6.85(1H,s), 7.01(2H,d,J=8.79 Hz),7.10(2H,d,J=8.79 Hz), 7.24-7.38(5H,m).

IR (KBr) cm⁻¹: 3434,3297,1642,1609,1510,1247,1177,1029, 831.

Example 116 Preparation of5,6-bis(4-methoxyphenyl)-2-[2-(4-methylpiperazino)ethyl]-2H-pyridazin-3-one(1) Preparation of5,6-bis(4-methoxyphenyl)-2-(2-hydroxyethyl)-2H-pyridazin-3-one

To a solution of 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one (154 mg,0.5 mmol) in N,N-dimethyl-formamide (0.03 ml), tetraethylammonium iodide(413 mg, 1.5 mmol) and ethylene carbonate (132 mg, 1.5 mmol) were added,followed by stirring at 145-150° C. for 2 hours. After the reactionmixture was allowed to cool down, water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The organiclayer was washed successively with water and a brine, and was then driedover anhydrous sodium sulfate. The solvent was distilled off and theresidue (100 mg) was separated and purified twice by chromatography on asilica gel column (silica gel: 4 g, ethyl acetate), whereby the titlecompound (165 mg, 94%) was obtained as a pale brown oil.

¹H-NMR (CDCl₃) δ: 3.58(1H,t,J=5.86 Hz), 3.80(3H,s), 3.81(3H,s),4.05-4.15(2H,m), 4.48(2H,dd,J=4.88,4.88 Hz), 6.79(2H,d,J=8.79 Hz),6.82(2H,d,J=8.79 Hz), 6.94(1H,s), 7.05(2H,d,J=8.79 Hz), 7.12(2H,d,J=9.28Hz).

(2) Preparation of5,6-bis(4-methoxyphenyl)-2-[2-(4-methylpiperazino)ethyl]-2H-pyridazin-3-one

To a solution of para-toluenesulfonyl chloride (357 mg, 4 eq) inpyridine (0.5 ml), a solution of5,6-bis(4-methoxyphenyl)-2-(2-hydroxyethyl)-2H-pyridazin-3-one (165 mg,0.47 mmol) in pyridine (1.0 ml) was added, followed by stirring at roomtemperature for 2 hours. The reaction mixture was poured into ice water,followed by extraction with ethyl acetate. The organic layer was washedsuccessively with water and a brine, and was then dried over anhydroussodium sulfate. The solvent was distilled off, and N-methylpiperazine(0.15 ml, 3 eq) was added to the residue. The resulting mixture wasstirred at 90-100° C. for 2 hours. After water was added to the reactionmixture, the mixture was extracted with ethyl acetate. The organic layerwas washed successively with water and a brine, and then dried overanhydrous sodium sulfate. The solvent was distilled off, and ethanol wasadded to the residue. The resulting mixture was azeotropically boiledthree times with ethanol to drive off water. The thus-obtained residue(256 mg) was separated and purified by chromatography on a silica gelcolumn [silica gel: 8 g, chloroform/methanol (20/1)], whereby a yellowoil (165 mg, 81%) was obtained. The oil was left over in a refrigerator.Precipitated crystals were washed with a mixed solvent of methanol anddiethyl ether, whereby the title compound (65 mg, 32%) was obtained aspale yellow prisms.

Melting point: 109.7-110.8° C.

¹H-NMR (CDCl₃) δ: 2.29(3H,s), 2.46(4H,brs), 2.64(4H,brs),2.87(2H,t,J=6.83 Hz), 3.80(3H,s), 3.81(3H,s), 4.40(2H,t,J=6.84 Hz),6.79(2H,d,J=9.03 Hz), 6.81(2H,d,J=8.78 Hz), 6.87(1H,s), 7.02(2H,d,J=8.79Hz), 7.12(2H,d,J=9.03 Hz).

IR (KBr) cm⁻¹: 1659,1608,1513,1295,1250,1177,1013.

Example 117 Preparation of5,6-bis(4-methoxyphenyl)-2-[2-(morpholino)ethyl]-2H-pyridazin-3-one

After 5,6-bis(4-methoxyphenyl)-2-(2-hydroxy-ethyl)-2H-pyridazin-3-onewas reacted with para-toluenesulfonyl chloride in a similar manner as inExample 116-(2), a further reaction was conducted with morpholine,whereby the title compound was obtained in a yield of 42.6%.

Pale yellow needles (methanol-diethyl ether).

Melting point: 145.1-145.8° C.

¹H-NMR (CDCl₃) δ: 2.59(4H,t,J=4.64 Hz), 2.86(2H,t,J=6.83 Hz),3.75(4H,t,J=4.64 Hz), 3.81(3H,s), 3.81(3H,s), 4.40(2H,t,J=7.08 Hz),6.79(2H,d,J=8.79 Hz), 6.81(2H,d,J=8.79 Hz), 6.88(1H,s), 7.05(2H,d,J=8.79Hz), 7.12(2H,d,J=8.78 Hz).

IR (KBr) cm⁻¹: 1664,1608,1513,1247,1181,1119,834.

Example 118 Preparation of5,6-bis(4-methoxyphenyl)-2-(2-(piperidino)ethyl]-2H-pyridazin-3-one

After 5,6-bis(4-methoxyphenyl)-2-(2-hydroxy-ethyl)-2H-pyridazin-3-onewas reacted with para-toluenesulfonyl chloride in a similar manner as inExample 116-(2), a further reaction was conducted with piperidine,whereby the title compound was obtained in a yield of 38.1%.

Yellow oil.

Mass (m/e): 419 (M⁺).

¹H-NMR (CDCl₃) δ: 1.44-1.46(2H,m), 1.56-1.64(4H,m), 2.52-2.56(4H,m),2.84(2H,t,J=7.33 Hz), 3.79(3H,s), 3.80(3H,s), 4.40(2H,t,J=7.33 Hz),6.78(2H,d,J=8.79 Hz), 6.81(2H,d,J=8.30 Hz), 6.87(1H,s), 7.04(2H,d,J=8.79Hz), 7.13(2H,d,J=8.79 Hz).

IR (film) cm⁻¹: 1660,1609,1514,1296,1250,1177,1033,834.

Example 119 Preparation of5,6-bis(4-methoxyphenyl)-2-(3-piperidylmethyl)-2H-pyridazin-3-one (1)Preparation of 3-(hydroxymethyl)-1-(tert-butoxy-carbony)piperidine

Triethylamine (2.8 ml, 20 mmol) was added to a solution of3-(hydroxymethyl)piperidine (1.15 g, 10 mmol) in tetrahydrofuran (15ml), followed by the addition of a solution of di-tert-butyl carbonate(2.62 g, 10 mmol) in tetrahydrofuran (5 ml) at room temperature understirring. The mixture was stirred at room temperature for 20 hours. Thesolvent was distilled off, and the residue was dissolved in ethylacetate (50 ml). The solution was washed successively with water and abrine, and was then dried over anhydrous sodium sulfate. The solvent wasthen distilled off, whereby the title compound (2.15 g, 100%) wasobtained as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.2-1.4(2H,m), 1.46(9H,s), 1.5-1.9(4H,m),2.8-3.3(2H,m), 3.51(2H,t,J=6.10 Hz), 3.6-3.9(2H,m).

IR (KBr) cm⁻¹: 3491,1742,1674,1428,1269,1177,1153,858, 769.

(2) Preparation of 1-(tert-butoxycarbonyl)-3-(tosyloxymethyl)piperidine

To a solution of 3-(hydroxymethyl)-1-(tert-butoxycarbonyl)piperidine(200 mg, 0.9,mmol) in anhydrous pyridine (4 ml), para-toluenesulfonicacid (890 mg) was added in small portions while stirring the solutionunder cooling with ice water. Five minutes later, the resultant mixturewas heated to room temperature, at which stirring was continued for 2hours. The reaction mixture was poured into ice water, followed byextraction with ethyl acetate. The organic layer was washed successivelywith water and a brine, and was then dried over anhydrous sodiumsulfate. The solvent was distilled off, whereby the title compound (343mg, 100%) was obtained as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.1-1.3(2H,m), 1.44(9H,m), 1.4-1.9(2H,m), 2.46(3H,s),2.7-2.9(1H,m), 3.8-4.1(4H,m), 3.89(2H,d,J=6.11 Hz), 7.35(2H,d,J=8.54Hz), 7.78(2H,d,J=8.30 Hz).

(3) Preparation of5,6-bis(4-methoxyphenyl)-2-[3-(1-tert-butoxycarbonyl)piperidyl)methyl)-2H-pyridazin-3-one

To a solution of 1-(tert-butoxycarbonyl)-3-(tosyloxymethyl)piperidine0(200 mg, 0.65 mmol) in N,N-dimethylformamide (4 ml),5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one (343 mg, 0.93 mmol) andpotassium carbonate (276 mg, 2.0 mmol) were added, followed by stirringat 80° C. for 8 hours. After the reaction mixture was allowed to cooldown, water was added to the reaction mixture. The mixture was extractedwith ethyl acetate. The organic layer was washed successively with water(twice) and a brine, and was then dried over anhydrous sodium sulfate.The solvent was distilled off and the resulting reddish brown oil (405mg) was then purified by silica gel preparative chromatography[chloroform/methanol (20/1)], whereby the title compound (383 mg,quantitative) was obtained as a pale brown oil.

¹H-NMR (CDCl₃) δ: 1.20-1.40(2H,m), 1.41(9H,s), 1.60-1.90(2H,m),2.15-2.35(1H,m), 2.65-2.90(2H,m), 3.80(3H,s), 3.81(3H,s),3.85-4.25(4H,m), 6.79(2H,d,J=8.79 Hz), 6.80(2H,d,J=8.78 Hz),7.04(2H,d,J=8.79 Hz), 7.13(2H,d,J=8.79 Hz).

(4) Preparation of5,6-bis(4-methoxyphenyl)-2-(3-piperidylmethyl)-2H-pyridazin-3-one

A 6 N aqueous solution of hydrochloric acid (0.2 ml, 1.2 mmol) was addedto a solution of5,6-bis(4-methoxyphenyl)-2-[3-(1-tert-butoxycarbonyl)-piperidyl)methyl]-2H-pyridazin-3-one(69 mg; content: 59 mg, 0.12 mmol) in tetrahydrofuran (2 ml), followedby stirring at 70° C. for 1 hour. After the reaction mixture was allowedto cool down, the solvent was distilled off and ethanol was added to theresidue. The thus-obtained mixture was azeotropically boiled three timeswith ethanol to drive off water. The residue (oil, 94 mg) was separatedand purified by silica gel preparative chromatography[chloroform/methanol (with 10% (W/W) ammonia) (30:1)], whereby the titlecompound (46 mg, 97.0%) was obtained as a pale yellow oil.

¹H-NMR (CDCl₃) δ: 1.20-1.40(1H,m), 1.40-1.58(1H,m), 1.65-1.80(1H,m),2.10-2.20(1H,m), 2.45-2.68(2H,m), 2.94-3.12(2H,m), 3.79(3H,s),3.81(3H,s), 4.04-5.04(2H,m), 6.78(2H,d,J=8.79 Hz), 6.81(2H,d,J=8.79 Hz),6.88(1H,s), 7.04(2H,d,J=8.54 Hz), 7.12(2H,d,J=8.55 Hz).

IR (KBr) cm⁻¹: 3313,3003,2935,2840,1668,1652,1609,1296,1251,1178,1030,834.

Example 120 Preparation of5,6-bis(4-methoxyphenyl)-2-[3-(1-methylpiperidyl)methyl]-2H-pyridazin-3-one

To a solution of5,6-bis(4-methoxyphenyl)-2-(3-piperidylmethyl)-2H-pyridazin-3-one (203mg, 0.5 mmol) in acetone/dimethyl sulfoxide (5/1) (6 ml), an acetonesolution of dimethyl sulfate (631 mg was dissolved with acetone into asolution of 5 ml in total volume) (1.0 ml, 1.0 mmol) was added, followedby stirring at 60° C. for 2 hours. After the reaction mixture wasallowed to cool down, water was added to the reaction mixture. Themixture was extracted with ethyl acetate. The organic layer was washedsuccessively with water and a brine and was then dried over anhydroussodium sulfate. The solvent was distilled off and the residue (oil, 115mg) was separated and purified by silica gel preparative chromatography(chloroform/methanol (with 10% (W/W) ammonia, (15:1)], whereby the titlecompound (63.2 mg, 30.0%) was obtained as a pale yellow oil.

¹H-NMR (CDCl₃) δ: 1.50-2.00(6H,m), 2.27(3H,s), 2.25-2.42(1H,m),2.73-2.87(2H,m), 3.80(3H,s), 3.81(3H,s), 4.10(1H,dd,J=6.35,12.69 Hz),4.21(1H,dd,J=7.81,12.69 Hz), 6.79(2H,d,J=8.79 Hz), 6.81(2H,d,J=8.55 Hz),6.88(1H,s), 7.05(2H,d,J=8.79 Hz), 7.12(2H,d,J=9.03 Hz).

IR (film) cm⁻¹: 1652,1610,1514,1464,1295,1248,1176, 1029,833,754.

Example 121 Preparation of2-benzyl-5-(4-chlorophenyl)-4,5-dihydro-6-(4-(methylthio)phenyl]-2H-pyridazin-3-one

Methyl 3-(4-chlorophenyl)-4-[4-(methylthio)-phenyl)-4-oxobutanoate (525mg, 1.505 mmol), benzyl hydrazine dihydrochloride (262.6 mg, 1.655 mmol)and sodium acetate (467.4 mg, 4.966 mmol) were dissolved in 85% ethanol(6 ml), followed by heating under reflux for 2 days. The reactionmixture was concentrated, to which a 2 N aqueous solution ofhydrochloric acid was added. The mixture was extracted with chloroform.The extract was washed with water and then dried over anhydrous sodiumsulfate. The solvent was distilled off and the thus-obtained residue wasseparated and purified by silica gel preparative chromatography[hexane/ethyl acetate (2/1)], whereby the title compound (290.3 mg,45.8%) was obtained.

Colorless prisms (ethyl acetate-hexane)

Melting point: 113.5-113.9° C.

Mass (m/e): 420,422 (M⁺).

¹H-NMR (CDCl₃) δ: 2.33(3H,s), 2.68(1H,d,J=16.47 Hz),2.86(1H,dd,J=7.42,16.47 Hz), 4.28(1H,d,J=7.42 Hz), 4.75(1H,d,14.06 Hz),5.29(1H,d,14.06 Hz), 6.79(2H,d,J=8.20 Hz), 7.03(2H,d,J=8.20 Hz),.7.11(2H,d,J=8.30 Hz), 7.17-7.29(3H,m), 7.31-7.38(2H,m), 7.58(2H,d,J=8.30Hz).

IR (KBr) cm⁻¹: 1659,1593,1387,1343,1141,729.

Example 122 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-chlorocinnamyl)-2H-pyridazine-3-thione

Lawesson's reagent (140 mg, 0.35 mmol) was added to a solution of5,6-bis(4-methoxyphenyl)-2-(4-chlorocinnamyl)-2H-pyridazin-3-one (146mg, 0.32 mmol) in toluene (5 ml), followed by stirring at 80° C. for 5hours under a nitrogen gas atmosphere. A saturated aqueous solution ofsodium hydrogencarbonate (10 ml) was added to the reaction mixture,followed by extraction with chloroform. The extract was washed with abrine, and then dried over anhydrous sodium sulfate. The solvent wasdistilled off, and the thus-obtained yellow oil (321 mg) was separatedand purified by chromatography on a silica gel column (silica gel: 36 g,chloroform), whereby the title compound (106 mg, 70.1%) was obtained.

Orange prisms (diethyl ether-hexane)

Melting point: 173.3-176.2° C.

¹H-NMR (CDCl₃) δ: 3.80(3H,s), 3.81(3H,s), 5.52(2H,d,J=6.58 Hz),6.57(1H,dt,J=15.86,6.60 Hz), 6.75(1H,d,J=15.86 Hz), 6.81(2H,d,J=9.03Hz), 6.82(2H,d,J=8.79 Hz), 7.07(2H,d,J=8.79 Hz), 7.89(2H,d,J=8.79 Hz),7.27(2H,d,J=8.54 Hz), 7.35(2H,d,J=8.54 Hz), 7.81(1H,s).

IR (KBr) cm⁻¹: 1608,1513,1397,1256,1178,1162,1257,1089, 836.

Example 123 Preparation of5,6-bis(4-methoxyphenyl)-2-benzyl-2H-pyridazine-3-thione

Using 5,6-bis(4-methoxyphenyl)-2-benzyl-2H-pyridazin-3-one as a startingmaterial, the procedures of Example 122 were repeated likewise, wherebythe title compound was obtained in a yield of 83.4%.

Yellow needles (ethyl acetate-hexane).

Melting point: 134.7-148.6° C.

Mass (m/e): 414 (M⁺).

¹H-NMR (CDCl₃) δ: 3.80(6H,s), 6.00(2H,s), 6.80(2H,d,J=9.03 Hz),6.81(2H,d,J=9.04 Hz), 7.06(2H,d,J=8.79 Hz), 7.16(2H,d,J=8.79 Hz),7.31-7.36(2H,m).

IR (KBr) cm⁻¹: 1607,1514,1396,1250,1174,1160,1153,1029, 833.

Example 124 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-fluorobenzyl)-2H-pyridazine-3-thione

Using 5,6-bis(4-methoxyphenyl)-2-(4-fluoro-benzyl)-2H-pyridazin-3-one asa starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 71.3%.

Yellow needles (ethyl acetate-diethyl ether).

Melting point: 137.1-137.8° C.

¹H-NMR (CDCl₃) δ: 3.81(6H,s), 5.95(2H,s), 6.80(4H,d,J=8.79 Hz),7.01-7.07(2H,m), 7.06(2H,d,J=8.79 Hz), 7.15(2H,d,J=8.79 Hz),7.31-7.36(3H,m), 7.60-7.65(2H,m) , 7.79(1H,s).

IR (KBr) cm⁻¹: 1609,1512,1397,1299,1253,1176,1154,1047, 832.

Example 125 Preparation of5,6-bis(4-methoxyphenyl)-2-(2,4-dichlorobenzyl)-2H-pyridazine-3-thione

Using 5,6-bis(4-methoxyphenyl)-2-(2,4-dichlorobenzyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 84.4%.

Yellow needles (ethyl acetate).

Melting point: 169.6-170.2° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.82(3H,s), 6.01(2H,s), 6.77(2H,d,J=8.78Hz), 6.83(2H,d,J=8.79 Hz), 7.10(2H,d,J=8.79 Hz), 7.12(2H,d,J=8.79 Hz),7.14(2H,d,J=8.30 Hz), 7.21(1H,dd,J=1.96,8.30 Hz), 7.45(1H,d,J=2.20 Hz),7.83(1H,s).

IR (KBr) cm⁻¹: 1609,1513,1472,1397,1297,1251,1177, 1162,1045,834.

Example 126 Preparation of5,6-bis(4-methoxyphenyl)-2-(2,4-difluorobenzyl)-2H-pyridazine-3-thione

Using5,6-bis(4-methoxyphenyl)-2-(2,4-difluoro-benzyl)-2H-pyridazin-3-one as astarting material, the title compound was obtained in a yield of 57.6%in a similar manner as in Example 122.

Yellow needles (ethyl acetate-diethyl ether).

Melting point: 175.4-175.7° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.81(3H,s), 5.98(2H,s), 6.78(2H,d,J=8.79Hz), 6.82(2H,d,J=8.79 Hz), 6.83-6.89(2H,m), 7.08(2H,d,J=8.79 Hz),7.13(2H,d,J=8.54 Hz), 7.47-7.56(1H,m), 7.80(1H,s).

IR (KBr) cm⁻¹: 1609,1514,1504,1397,1300,1252,1174, 1156,1046,833.

Example 127 Preparation of5,6-bis(4-methoxyphenyl)-2-(3,4,5-trimethoxybenzyl)-2H-pyridazine-3-thione

Using5,6-bis(4-methoxyphenyl)-2-(3,4,5-trimethoxybenzyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 35.1%.

Yellow prisms (ethyl acetate-diethyl ether).

Melting point: 142.4-146.4° C.

¹H-NMR (CDCl₃) δ: 3.81(6H,s), 3.84(3H,s), 3.87(6H,s), 5.92(2H,s),6.80(2H,d,J=9.03 Hz), 6.81(2H,d,J=9.03 Hz), 6.97(2H,s), 7.06(2H,d,J=8.79Hz), 7.15(2H,d,J=8.79 Hz), 7.80(1H,s).

IR (KBr) cm⁻¹: 1606,1511,1459,1423,1250,1127,1033,842.

Example 128 Preparation of5,6-bis(4-methoxyphenyl)-2-(3-pyridylmethyl)-2H-pyridazine-3-thione

Using 5,6-bis(4-methoxyphenyl)-2-(3-pyridyl-methyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 86.7%.

Yellow brown prisms.

Melting point: 162.7-163.7° C.

¹H-NMR (CDCl₃) δ: 3.81(6H,s), 6.00(2H,s), 6.80(2H,d,J=8.79 Hz),6.81(2H,d,J=9.04 Hz), 7.06(2H,d,J=9.03 Hz), 7.15(2H,d,J=9.03 Hz),7.29(1H,dd,J=4.88,7.81 Hz), 7.79(1H,s), 8.02(1H,d,J=8.06 Hz),8.57(1H,dd,J=1.46,4.76 Hz), 8.86(1H,d,J=1.46).

IR (KBr) cm⁻¹: 1608,1514,1397,1249,1181,1152,1020,837.

Example 129 Preparation of5,6-bis(4-methoxyphenyl)-2-(4-pyridylmethyl)-2H-pyridazine-3-thione

Using 5,6-bis(4-methoxyphenyl)-2-(4-pyridyl-methyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 84.5%.

Yellow brown prisms (methanol-ethyl acetate).

Melting point: 159.6-159.9° C.

¹H-NMR (CDCl₃) δ: 3.81(3H,s), 3.82(3H,s), 5.98(2H,s), 6.81(2H,d,J=9.03Hz), 6.82(2H,d,J=9.03 Hz)., 7.09(2H,d,J=9.04 Hz), 7.15(2H,d,J=8.79 Hz),7.40(2H,d,J=6.10 Hz), 7.81(1H,s), 8.60(2H,d,J=5.86 Hz).

In a manner known per se in the art, the methane-sulfonate of the titlecompound was obtained in a yield of 56.7%.

Yellow prisms (methanol-ethyl acetate).

Melting point: 198.5-199.8° C.

¹H-NMR (CDCl₃) δ: 2.89(3H,s), 3.82(3H,s), 3.82(3H,s), 6.14(2H,s),6.82(2H,d,J=9.03 Hz), 6.84(2H,d,J=9.04 Hz), 7.10(2H,d,J=9.04 Hz),7.16(2H,d,J=9.04 Hz), 7.79(1H,s), 7.95(2H,d,J=6.83 Hz), 8.86(2H,d,J=6.59Hz).

IR (KBr) cm⁻¹: 1640,1606,1511,1396,1247,1175,1152,1027, 838,800,769.

Example 130 Preparation of5,6-bis(4-methoxyphenyl)-2-(2,4-difluorocinnamyl)-2H-pyridazine-3-thione

Using5,6-bis(4-methoxyphenyl)-2-(2,4-difluorocinnamyl)-2H-pyridazin-3-one asa starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 40.6%.

Yellow needles (ethyl acetate-diethyl ether).

Melting point: 140.7-141.4° C.

¹H-NMR (CDCl₃) δ: 3.80(3H,s), 3.81(3H,s), 5.54(2H,d,J=6.59 Hz),6.54(1H,dt,J=16.11,6.59 Hz), 6.75-6.82(2H,m), 6.81(2H,d,J=9.03 Hz),6.82(2H,d,J=9.04 Hz), 6.89(1H,d,J=16.12 Hz), 7.08(2H,d,J=8.79 Hz),7.19(2H,d,J=9.03 Hz), 7.43-7.51(1H,m), 7.81(1H,s).

IR (KBr) cm⁻¹: 1608,1502,1398,1255,1237,1180,1154,1035, 963,835.

Example 131 Preparation of5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2-cyclopropylmethyl-2H-pyridazine-3-thione

Using5-(4-chlorophenyl)-6-[4-(methylthio)-phenyl]-2-cyclopropylmethyl-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 64.5%.

Yellow prisms (ethyl acetate-hexane).

Melting point: 135.3-135.4° C.

Mass (m/e): 398,400 (M⁺).

¹H-NMR (CDCl₃) δ: 0.54-0.62(4H,m), 1.68-1.75(1H,m), 4.63(2H,d,J=7.42Hz), 7.10(2H,d,J=8.20 Hz), 7.14(4H,s), 7.30(2H,d,J=8.20 Hz), 7.81(1H,s).

IR (KBr) cm⁻¹: 1600,1490,1477,1129,1101,828.

Example 132 Preparation of2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazine-3-thione

Using2-benzyl-5-(4-chlorophenyl)-6-[4-(methyl-thio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 77.6%.

Yellow needles (ethyl acetate-hexane).

Melting point: 103.2-103.3° C.

Mass (m/e): 434,436 (M⁺).

¹H-NMR (CDCl₃) δ: 2.48(3H,s), 5.99(2H,s), 7.07-7.14(8H,m),7.26-7.39(3H,m), 7.60(2H,d,J=6.64 Hz), 7.79(1H,s).

IR (KBr) cm⁻¹: 1597,1491,1413,1345,1145,1100,825.

Example 133 Preparation of5-(4-chlorophenyl)-2-(2,4-difluoro-benzyl)-6-(4-(methylthio)phenyl]-2H-pyridazine-3-thione

Using5-(4-chlorophenyl)-2-(2,4-difluorobenzyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 65.6%.

Yellow needles (ethyl acetate-hexane).

Melting point: 176.5-176.6° C.

Mass (m/e): 470,472 (M⁺).

¹H-NMR (CDCl₃) δ: 2.47(3H,s), 5.97(2H,s), 6.86(2H,t,J=8.30 Hz),7.05-7.12(6H,m), 7.30(2H,d,J=8.59 Hz), 7.53(1H,dd,J=14.64,8.20 Hz),7.80(1H,s).

IR (KBr) cm⁻¹: 1604,1506,1410,1336,1154,1101,1089,829.

Example 134 Preparation of5-(4-chlorophenyl)-2-(2,4-dichloro-benzyl)-6-[4-(methylthio)phenyl]-2H-pyridazine-3-thione

Using5-(4-chlorophenyl)-2-(2,4-dichlorobenzyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 77.2%.

Yellow needles (ethyl acetate-hexane).

Melting point: 183.2-183.4° C.

Mass (m/e): 502 (M⁺).

¹H-NMR (CDCl₃) δ: 2.46(3H,s), 6.00(2H,s), 7.04-7.32(10H,m),7.46(1H,d,J=2.15 Hz), 7.82(1H,s).

IR (KBr) cm⁻¹: 1594,1477,1409,1138,1099,824.

Example 135 Preparation of5-(4-chlorophenyl)-6-(4-(methylthio)-phenyl]-2-(3-pyridylmethyl)-2H-pyridazine-3-thione

Using5-(4-chlorophenyl)-6-(4-(methylthio)-phenyl]-2-(3-pyridylmethyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 99%.

Yellow needles (ethyl acetate-hexane).

Melting point: 130.3-131.0° C.

Mass (m/e): 435,437 (M⁺).

¹H-NMR (CDCl₃) δ: 2.48(3H,s), 5.99(2H,s), 7.06-7.15(6H,m),7.29-7.31(3H,m), 7.78(1H,s), 8.05(1H,d,J=8.20 Hz), 8.58(1H,d,J=3.32 Hz),8.86(1H,s).

IR (KBr) cm⁻¹: 1596,1413,1147,1101,826.

Example 136 Preparation of5-(4-fluorophenyl)-6-(4-(methylthio)-phenyl]-2H-pyridazine-3-thione

Using 5-(4-fluorophenyl)-6-(4-(methylthio)-phenyl]-2H-pyridazin-3-one asa starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 84.3%.

Yellow prisms (ethyl acetate-hexane).

Melting point: 218.7-218.9° C.

Mass (m/e): 328 (M⁺).

¹H-NMR (CDCl₃) δ: 2.47(3H,s), 7.03(2H,t,J=8.59 Hz), 7.09-7.16(6H,m).

IR (KBr) cm⁻¹: 3133,1605,1597,1509,1388,1318,1109, 842,827.

Example 137 Preparation of2-cyclopropylmethyl-5-(4-fluoro-phenyl)-6-[4-(methylthio)phenyl]-2H-pyridazine-3-thione

Using2-cyclopropylmethyl-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 95.6%.

Yellow prisms (ethyl acetate-hexane).

Melting point: 135.7-135.8° C.

Mass (m/e): 382 (M⁺).

¹H-NMR (CDCl₃) δ: 0.54-0.64(4H,m), 1.67-1.77(1H,m), 2.47(3H,s),4.64(2H,d,J=7.32 Hz), 7.02(2H,t,J=8.66 Hz), 7.09-7.17(6H,m), 7.81(1H,s).

IR (KBr) cm⁻¹: 1605,1509,1476,1412,1230,1158,1101,843.

Example 138 Preparation of2-benzyl-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazine-3-thione

Using2-benzyl-5-(4-fluorophenyl)-6-[4-(methyl-thio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was-obtained in a yield of 95.6%.

Yellow prisms (diethyl ether-hexane).

Melting point: 108.1-108.2° C.

Mass (m/e): 418 (M⁺).

¹H-NMR (CDCl₃) δ: 2.46(3H,s), 5.99(2H,s), 6.97-7.14(7H,m),7.32-7.37(3H,m), 7.60(2H,d,J=6.10 Hz), 7.79(1H,s).

IR (KBr) cm⁻¹: 1605,1509,1417,1162,1101,836.

Example 139 Preparation of2-benzyl-5-(4-fluorophenyl)-6-(4-(methylsulfonyl)phenyl]-2H-pyridazine-3-thione

Using2-benzyl-5-(4-fluorophenyl)-6-[4-(methyl-sulfonyl)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 100%.

Yellow prisms (ethyl acetate-hexane).

Melting point: 181.8-182.0° C.

Mass (m/e): 450 (M⁺).

¹H-NMR (CDCl₃) δ: 3.06(3H,s), 5.99(2H,s), 7.00-7.11(4H,m),7.30-7.42(5H,m), 7.58(2H,dd,J=8.01,1.56 Hz), 7.84(1H,s),7.87(2H,d,J=10.35 Hz).

IR (KBr) cm⁻¹: 1604,1511,1308,1163,1152,1083,848,571.

Example 140 Preparation of5-(4-fluorophenyl)-2-(4-methoxy-benzyl)-6-[4-(methylthio)phenyl]-2H-pyridazine-3-thione

Using5-(4-fluorophenyl)-2-(4-methoxybenzyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 92.2%.

Yellow powder (ethyl acetate-hexane).

Melting point: 112.7-112.9° C.

Mass (m/e): 448 (M⁺).

¹H-NMR (CDCl₃) δ: 2.47(3H,s), 3.79(3H,s), 5.92(2H,s), 6.89(2H,d,J=8.54Hz), 6.99(2H,d,J=8.54 Hz), 7.09-7.14(6H,m), 7.60(2H,d,J=8.54 Hz),7.78(1H,s).

IR (KBr) cm⁻¹: 1607,1511,1248,1162,1101.

Example 141 Preparation of2-(2,4-dichlorobenzyl)-5-(4-fluoro-phenyl)-6-[4-(methylthio)phenyl]-2H-pyridazine-3-thione

Using2-(2,4-dichlorobenzyl)-5-(4-fluorophenyl)-6-(4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 79.8%.

Yellow needles (ethyl acetate-hexane).

-Melting point: 154.0-154.2° C.

Mass (m/e): 487 (M⁺).

3H-NMR (CDCl₃) δ: 2.45(3H,s), 6.00(2H,s), 7.00-7.10(6H,m),7.13-7.22(4H,m), 7.45(1H,d,J=1.95 Hz), 7.82(1H,s).

IR (KBr) cm⁻¹: 1597,1509,1414,1099,839,824.

Example 142 Preparation of2-(4-chlorobenzyl)-6-(4-methoxy-phenyl)-5-(4-pyridyl)-2H-pyridazine-3-thione

Using2-(4-chlorobenzyl)-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 122 were repeatedlikewise, whereby the title compound was obtained in a yield of 45.3%.

Yellow prisms (chloroform-hexane).

Melting point: 144.4-145.1° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 5.92(2H,s), 6.81(2H,d,J=8.90 Hz),7.05(2H,dd,J=1.65,4.45 Hz), 7.11(2H,d,J=8.90 Hz), 7.31(2H,d,J=8.42 Hz),7.55(2H,d,J=8.42 Hz), 7.77(1H,s), 8.57(2H,dd,J=1.65,4.45 Hz).

IR (KBr) cm⁻¹: 1609,1516,1491,1477,1416,1399,1343, 1252,1163,1146.

Example 143 Preparation of6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazine-3-thione

To a solution of sodium periodate (1.66 g) in water (10 ml), sulfuricacid (0.163 me) was added under ice cooling, followed by the addition ofa solution of tartaric acid (1.16 g) in water (3 ml). The resultingsolution was stirred at room temperature for 30 minutes. Added to thesolution were 3′-fluoro-4′-methoxy-2-(4-methoxyphenyl)acetophenone (2.12g, 7.73 mmol), a solution of sodium hydroxide (0.92 g) in water (15 ml)and ethanol (20 ml), followed by stirring overnight at room temperature.After the mixture was heated at 70° C. for 40 minutes, the ethanol wasdistilled off, and water was then added. The mixture was washed withethyl acetate. The water layer was acidified with hydrochloric acid,followed by extraction with ethyl acetate. The extract was washedsuccessively with water and a brine, and was then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The crude oil (1.29 g) was dissolved in ethanol (50 ml) and subsequentto addition of hydrazine hydrate (356 mg), the resultant mixture washeated overnight under reflux. A 2 N aqueous solution of sodiumhydroxide (40 ml) was added to the reaction mixture, followed by heatingunder reflux for 2 hours. After the reaction mixture was neutralizedwith hydrochloric acid, the thus-obtained mixture was extracted withethyl acetate. The organic layer was washed with a brine and was thendried over anhydrous sodium sulfate. The solvent was distilled off. Theresidue was separated and purified by chromatography on a silica gelcolumn and was then crystallized from ethanol, whereby the titlecompound (764 mg, 30.3%) was obtained as yellow prisms.

Melting point: 221.8-223.0° C.

Mass (m/Z): 326 (M⁺).

¹H-NMR (CDCl₃) δ: 3.82(3H,s), 3.88(3H,s), 6.80-6.87(3H,m),6.91(1H,ddd,J=8.5,2.2,1.0 Hz), 6.94(1H,s), 6.98(1H,dd,J=12.0,2.2 Hz),7.06(2H,d,J=9.0 Hz), 1l.90(1H,brs).

IR (KBr) cm⁻¹: 1652,1610,1515,1311,1298,1271,1261,1249, 1025.

Example 144 Preparation of2-benzyl-6-(3-fluoro-4-methoxy-phenyl)-5-(4-methoxyphenyl)-2H-pyridazin-3-one

Using6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxy-phenyl)-2H-pyridazin-3-one andbenzyl bromide as starting materials, the procedures of Example 12 wererepeated likewise, whereby the title compound was obtained in a yield of95.8%.

Pale yellow prisms (ethyl acetate-hexane).

Melting point: 136.6-137.8° C.

Mass (m/Z): 416 (M⁺).

¹H-NMR (CDCl₃) δ: 3.81(3H,s), 3.87(3H,s), 5.41(2H,s), 6.76-6.83(3H,m),6.85(1H,dd,J=8.5,2.0 Hz), 6.88(1H,s), 6.97(1H,dd,J=12.0,2.0 Hz),7.02(2H,d,J=8.5 Hz), 7.27-7.41(3H,m), 7.53(2H,d,J=7.1 Hz).

IR (KBr) cm⁻¹: 1671,1610,1519,1511,1432,1304,1292,1275, 1249,1177,822.

Example 145 Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-5- (4-methoxyphenyl)-2H-pyridazin-3-one

Using6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxy-phenyl)-2H-pyridazin-3-one and4-chlorocinnamyl chloride as starting materials, the procedures ofExample 12 were repeated likewise, whereby the title compound wasobtained in a yield of 72.5%.

Colorless crystalline powder (ethyl acetate-hexane).

Melting point: 144.0-145.4° C.

Mass (m/Z): 476 (M⁺).

¹H-NMR (CDCl₃) δ: 3.81(3H,s), 3.87(3H,s), 4.99(2H,d,J=6.6 Hz),6.44(1H,dt,J=15.9,6.6 Hz), 6.69(1H,d,J=15.9 Hz), 6.79-6.90(4H,m),6.91(1H,s), 7.01(1H,dd,J=12.2,2.0 Hz), 7.04(2H,d,J=8.5 Hz),7.27(2H,d,J=8.5 Hz), 7.32(2H,d,J=8.5 Hz).

IR (KBr) cm⁻¹: 1666,1610,1520,1512,1279,1247.

Example 146 Preparation of2-ethyl-6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-3-one

To a solution of6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-3-one (150mg, 0.46 mmol) in N,N-dimethylformamide (1.5 ml), potassium carbonate(317.6 mg) and ethyl iodide (179.2 mg) were added, followed by stirringat 70° C. for 3 hours. The reaction mixture was concentrated, followedby the addition of water. The mixture was extracted with ethyl acetate,and the extract was dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The residue was separated andpurified by preparative silica gel chromatography and then crystallizedfrom ethyl acetate-hexane, whereby the title compound (156 mg, 95.8%)was obtained as pale yellow needles.

Melting point: 122.6-123.5° C.

Mass (m/Z): 354 (M⁺).

¹H-NMR (CDCl₃) δ: 1.46(3H,t,J=7.2 Hz), 3.81(3H,s), 3.87(3H,s),4.30(2H,q,J=7.2 Hz), 6.79-6.86(3H,m), 6.87-6.92(2H,m),7.01(1H,dd,J=12.2,2.0 Hz), 7.04(2H,d,J=8.8 Hz).

IR (KBr) cm⁻¹: 1659,1609,1520,1512,1305,1297,1277,1244,1181,1131,1022,837.

Example 147 Preparation of6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-5-(4-methoxyphenyl)-2H-pyridazin-3-one

Using6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxy-phenyl)-2H-pyridazin-3-one andisobutyl bromide as starting materials, the procedures of Example 146were repeated likewise, whereby the title compound was obtained in ayield of 91.3%.

Colorless needles (diethyl ether-hexane).

Melting point: 86.8-87.4° C.

Mass (m/Z): 382 (M⁺).

¹H-NMR (CDCl₃) δ: 1.01(6H,d,J=6.8 Hz), 2.37(1H,tsep,J=7.3,6.8 Hz),3.81(3H,s), 3.87(3H,s), 4.08(2H,d,J=7.3 Hz), 6.79-6.86(3H,m),6.87(1H,dd, J=2.1,0.6 Hz), 6.89(1H,s), 7.00(1H,dd,J=12.1,2.1 Hz),7.05(2H,d,J=9.0 Hz).

IR (KBr) cm⁻¹: 1660,1610,1521,1512,1305,1297,1277, 1245,1177.

Example 148 Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-5- (4-methoxyphenyl)-2H-pyridazin-3-one

Using6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxy-phenyl)-2H-pyridazin-3-one and(chloromethyl)cyclo-propane as starting materials, the procedures ofExample 146 were repeated likewise, whereby the title compound wasobtained in a yield of 93.0%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 132.2-132.6° C.

Mass (m/Z): 380 (M⁺).

¹H-NMR (CDCl₃) 6: 0.46-0.62(4H,m), 1.45(1H,ttt,J=7.8,7.3,4.9 Hz),3.82(3H,s), 3.87(3H,s), 4.11(2H,d,J=7.3 Hz), 6.80-6.91(5H,m),7.01(1H,dd,J=12.2,2.0 Hz), 7.06(2H,d,J=9.0 Hz).

IR (KBr) cm⁻¹: 1660,1612,1521,1511,1306,1295,1278,1244, 1176,1019,828.

Example 149 Preparation of4,5-dihydro-5-(3-fluoro-4-methoxy-phenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using ethyl3-(3-fluoro-4-methoxyphenyl)-4-(4-methoxyphenyl)-4-oxobutanoate as astarting material, the procedures of Example 1 were repeated likewise,whereby the title compound was obtained in a yield of 55.3%.

Pale yellow scales (ethyl acetate-hexane).

Melting point: 171.2-173.4° C.

Mass (m/Z): 328 (M⁺).

¹H-NMR (CDCl₃) δ: 2.75(1H,dd,J=16.8,1.2 Hz), 2.97(1H,dd,J=16.8,7.7 Hz),3.82(3H,s), 3.85(3H,s), 4.40(1H,dd,J=7.6,1.2 Hz), 6.85-6.98(5H,m),7.64(2H,d,J=8.8 Hz), 8.54(1H,brs).

IR (KBr) cm⁻¹: 1675,1660,1616,1516,1351,1278,1255,1174.

Example 150 Preparation of5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using4,5-dihydro-5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 7 were repeatedlikewise, whereby the title compound was obtained in a yield of 90.2%.

Colorless needles (ethyl acetate-hexane).

Melting point: 212.8-213.4° C.

Mass (m/Z): 326 (M⁺).

¹H-NMR (CDCl₃) δ: 3.80(3H,s), 3.89(3H,s), 6.79(2H,d,J=8.8 Hz),6.85(l,d,J=11.7 Hz), 6.87-6.93(2H,m), 6.96(1H,s), 7.13(2H,d,J=8.8 Hz),12.75(1H,brs).

IR (KBr) cm⁻¹: 1667,1614,1520,1308,1278,1254,1132,1022, 835.

Example 151 Preparation of2-benzyl-5-(3-fluoro-4-methoxy-phenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxy-phenyl)-2H-pyridazin-3-one andbenzyl bromide as starting materials, the procedures of Example 12 wererepeated likewise, whereby the title compound was obtained in a yield of95.6%.

Colorless needles (ethyl acetate-hexane).

Melting point: 109.6-111.6° C.

Mass (m/Z): 416 (M⁺).

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.87(3H,s), 5.41(2H,s), 6.76-6.89(6H,m),7.10(2H,d,J=8.8 Hz), 7.27-7.38(3H,m), 7.50-7.55(2H,m).

IR (KBr) cm⁻¹: 1667,1608,1516,1462,1295,1276,1248,1181, 1131,1021,873.

Example 152 Preparation of2-(4-chlorocinnamyl)-5-(3-fluoro-4-methoxyphenyl)-6- (4-methoxyphenyl)-2H-pyridazin-3-one

Using5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxy-phenyl)-2H-pyridazin-3-one and4-chlorocinnamyl chloride as starting materials, the procedures ofExample 12 were repeated likewise, whereby the title compound wasobtained in a yield of 58.7%.

Colorless crystalline powder (ethyl acetate-hexane).

Melting point: 109.2-111.0° C.

Mass (m/Z): 476 (M⁺).

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.88(3H,s), 4.99(2H,d,J=6.6 Hz),6.44(1H,dt,J=15.9,6.6 Hz), 6.68(1H,d,J=15.9 Hz), 6.80(2H,d,J=9.0 Hz),6.82-6.90(3H,m), 6.91(1H,s), 7.13(2H,d,J=9.0 Hz), 7.26(2H,d,J=8.5 Hz),7.32(2H,d,J=8.5 Hz).

IR (KBr) cm⁻¹: 1655,1611,1515,1491,1306,1275,1250,1177, 1129.

Example 153 Preparation of2-ethyl-5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxy-phenyl)-2H-pyridazin-3-one andethyl iodide as starting materials, the procedures of Example 146 wererepeated likewise, whereby the title compound was obtained in a yield of97.8%.

Colorless needles (ethyl acetate-hexane).

Melting point: 161.7-162.2° C.

Mass (m/Z): 354 (M⁺).

¹H-NMR (CDCl₃) δ: 1.46(3H,t,J=7.1 Hz), 3.80(3H,s), 3.89(3H,s),4.31(2H,q,J=7.1 Hz), 6.78-6.92(6H,m), 7.13(1H,d,J=8.8 Hz).

IR (KBr) cm⁻¹: 1655,1612,1519,1515,1305,1297,1278,1252,1175,1130,1022,833.

Example 154 Preparation of5-(3-fluoro-4-methoxyphenyl)-2-isobutyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxy-phenyl)-2H-pyridazin-3-one andisobutyl iodide as starting materials, the procedures of Example 146were repeated likewise, whereby the title compound was obtained in ayield of 75.1%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 124.6-125.0° C.

Mass (m/Z): 382 (M⁺).

¹H-NMR (CDCl₃) δ: 1.01(6H,d,J=6.8 Hz), 2.37(1H,tsep,J=7.6,6.8 Hz),3.80(3H,s), 3.89(3H,s), 4.08(2H,d,J=7.6 Hz), 6.80(2H,d,J=9.0 Hz),6.84(1H,dd,J=11.3,1.3 Hz), 6.87-6.91(3H,m), 7.12(2H,d,J=9.0 Hz).

IR (KBr) cm⁻¹: 1660,1612,1517,1463,1443,1308,1299,1281,1251,1238,1178,1133,1023.

Example 155 Preparation of2-cyclopropylmethyl-5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxy-phenyl)-2H-pyridazin-3-one and(chloromethyl)cyclo-propane as starting materials, the procedures ofExample 146 were repeated likewise, whereby the title compound wasobtained in a yield of 93.8%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 135.2-135.7° C.

Mass (m/Z): 380 (M⁺).

¹H-NMR (CDCl₃) δ: 0.46-0.62(4H,m), 1.42(1H,ttt,J=7.8,7.3,4.9 Hz),3.80(3H,s), 3.89(3H,s), 4.11(2H,d,J=7.3 Hz), 6.80(2H,d,J=8.8 Hz),6.82-6.93(4H,m), 7.13(2H,d,J=8.8 Hz).

IR (KBr) cm⁻¹: 1661,1611,1586,1519,1309,1295,1282,1249,1181,1130,1021,823.

Example 156 Preparation of5,6-bis(3-fluoro-4-methoxyphenyl)-4,5-dihydro-2H-pyridazin-3-one

Using ethyl 3,4-bis(3-fluoro-4-methoxyphenyl)-4-oxobutanoate as astarting material, the procedures of Example 1 were repeated likewise,whereby the title compound was obtained in a yield of 22.9%.

Colorless needles (ethyl acetate-hexane).

Melting point: 195.7-197.7° C.

Mass (m/Z): 346 (M⁺).

¹H-NMR (CDCl₃) δ: 2.76(1H,d,J=17.1 Hz), 2.97(1H,dd,J=17.1,7.6 Hz),3.85(3H,s), 3.89(3H,s), 4.35(1H,d,J=7.6 Hz), 6.84-6.95(4H,m),7.35(1H,d,J=8.8 Hz), 7.51(1H,dd,J=12.6,1.6 Hz), 8.71(1H,brs).

IR (KBr) cm⁻¹: 1661,1622,1519,1351,1279.

Example 157 Preparation of5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Using 5,6-bis(3-fluoro-4-methoxyphenyl)-4,5-dihydro-2H-pyridazin-3-oneas a starting material, the procedures of Example 7 were repeatedlikewise, whereby the title compound was obtained in a yield of 94.9%.

Yellow prisms (chloroform-methanol-hexane).

Melting point: 204.8-205.7° C.

Mass (m/Z): 344 (M⁺).

¹H-NMR (CDCl₃) δ: 3.89(3H,s), 3.91(3H,s), 6.81-6.95(6H,m),6.97(1H,dd,J=12.0,2.2 Hz), 12.04(1H,brs).

IR (KBr) cm⁻¹: 1652,1618,1589,1519,1439,1308,1278,1139, 1128,1023,815.

Example 158 Preparation of2-benzyl-5,6-bis(3-fluoro-4-methoxy-phenyl)-2H-pyridazin-3-one

Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one and benzylbromide as starting materials, the procedures of Example 12 wererepeated likewise, whereby the title compound was obtained in a yield of99.9%.

Colorless prisms (ethyl acetate-hexane).

Melting point: 114.1-115.2° C.

Mass (m/Z): 434 (M⁺).

¹H-NMR (CDCl₃) δ: 3.88(3H,s), 3.89(3H,s), 5.40(2H,s), 6.78-7.01(7H,m),7.28-7.39(3H,m), 7.52(2H,dd,J=8.2,1.3 Hz).

IR (KBr) cm⁻¹: 1671,1517,1430,1424,1308,1276,1130.

Example 159 Preparation of5,6-bis(3-fluoro-4-methoxyphenyl)-2-(4-chlorocinnamyl)-2H-pyridazin-3-one

Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one and4-chlorocinnamyl chloride as starting materials, the procedures ofExample 12 were repeated likewise, whereby the title compound wasobtained in a yield of 42.9%.

Yellow crystalline powder (diethyl ether-hexane).

Melting point: 72.5-74.9° C.

Mass (m/Z): 494 (M⁺).

¹H-NMR (CDCl₃) δ: 3.88(3H,s), 3.90(3H,s), 4.99(2H,d,J=6.6 Hz),6.43(1H,dt,J=15.9,6.6 Hz), 6.69(1H,d,J=15.9 Hz), 6.80-6.95(6H,m),6.99(1H,dd,J=12.1,1.8 Hz), 7.27(2H,d,J=8.5 Hz), 7.32(2H,d,J=8.5 Hz).

IR (KBr) cm⁻¹: 1664,1619,1589,1520,1491,1440,1307, 1278,1133,1025.

Example 160 Preparation of5,6-bis(3-fluoro-4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one

Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one and ethyliodide as starting materials, the procedures of Example 146 wererepeated likewise, whereby the title compound was obtained in a yield of97.2%.

Colorless needles (ethyl acetate-hexane).

Melting point: 177.8-178.5° C.

Mass (m/Z): 372 (M⁺)

¹H-NMR (CDCl₃) δ: 1.46(3H,t,J=7.1 Hz), 3.89(3H,s), 3.91(3H,s),4.30(2H,q,J=7.1 Hz), 6.79-6.95(6H,m), 7.00(1H,dd,J=11.1,1.8 Hz).

IR (KBr) cm⁻¹: 1655,1519,1306,1286,1275,1133,1127,1023.

Example 161 Preparation of5,6-bis(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one and isobutyliodide as starting materials, the procedures of Example 146 wererepeated likewise, whereby the title compound was obtainedquantitatively.

Colorless prisms (ethyl acetate-hexane).

Melting point: 154.0-154.5° C.

Mass (m/Z): 400 (M⁺).

¹H-NMR (CDCl₃) δ: 1.01(6H,d,J=6.8 Hz), 2.36(1H,tsep,J=7.3,6.8 Hz),3.89(3H,s), 3.91(3H,s), 4.08(2H,d,J=7.3 Hz), 6.81-6.94(6H,m),6.99(1H,dd,J=12.3,1.8 Hz).

IR (KBr) cm⁻¹: 1660,1521,1438,1308,1289,1274,1134,1021.

Example 162 Preparation of5,6-bis(3-fluoro-4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazin-3-one

Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one and(chloromethyl)cyclopropane as starting materials, the procedures ofExample 146 were repeated likewise, whereby the title compound wasobtained quantitatively.

Colorless prisms (ethyl acetate-hexane).

Melting point: 142.3-142.7° C.

Mass (m/Z): 398 (M⁺).

¹H-NMR (CDCl₃) δ: 0.45-0.52(2H,m), 0.54-0.62(2H,m),1.44(1H,ttt,J=7.6,7.3,4.9 Hz), 3.89(3H,s), 3.91(3H,s), 4.11(2H,d,J=7.3Hz), 6.81-6.94(6H,m), 7.00(1H,dd,J=12.1,1.8 Hz).

IR (KBr) cm⁻¹: 1660,1590,1522,1515,1447,1427,1308,1278,1145,1129,1018,862,761.

Example 163 Preparation of5,6-bis(4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one

Ethyl iodide (280 mg, 1.8 mmol) was added to a suspension of5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one (463 mg, 1.5 mmol) andpotassium carbonate (311 mg, 2.25 mmol) in N,N-dimethylformamide (5 ml),followed by heating at 70° C. under stirring for 9.5 hours. Water wasadded to the reaction mixture, and the thus-obtained mixture wasextracted with ethyl acetate. The extract was washed successively withwater and a brine, and was then dried over anhydrous sodium sulfate. Thesolvent was distilled off, and the residue so obtained was separated andpurified by chromatography on a silica gel column (silica gel: 11 g),whereby yellow crystals (466 mg) were obtained. The crystals wererecrystallized from ethyl acetate-n-hexane, whereby the title compound(360 mg, 78.3%) was obtained as pale yellow prisms.

Melting point: 142.8-143.4° C.

¹H-NMR (CDCl₃) δ: 1.46(3H,t,J=7.08 Hz), 3.80(3H,s), 3.81(3H,s),4.31(2H,q,J=7.08 Hz), 6.79(2H,d,J=9.03 Hz), 6.81(2H,d,J=8.79 Hz),6.89(1H,s), 7.04(2H,d,J=8.79 Hz), 7.14(2H,d,J=9.03 Hz).

IR (KBr) cm⁻¹: 3447,1656,1608,1513,1294,1249,1183,1023, 840.

Example 164 Preparation of5,6-bis(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one

Similarly to Example 163, the title compound was obtained in a yield of100%.

Colorless oil.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.80(3H,s), 3.88(3H,s), 6.79(2H,d,J=8.79Hz), 6.81(2H,d,J=8.79 Hz), 6.91(1H,s), 7.04(2H,d,J=8.78 Hz),7.14(2H,d,J=9.03 Hz).

IR (film) cm⁻¹: 3479,2972,2937,2839,1660,1609,1514,1296,1247,1180,1032,997,834.

Example 165 Preparation of5,6-bis(4-methoxyphenyl)-2-isopropyl-2H-pyridazin-3-one

Similarly to Example 163, the title compound was obtained in a yield of100%.

Pale yellow amorphous.

¹H-NMR (CDCl₃) δ: 1.44(6H,d,J=6.54 Hz), 3.80(3H,s), 3.81(3H,s),5.39(1H,seplet,J=6.60 Hz), 6.79(2H,d,J=8.79 Hz), 6.83(2H,d,J=8.79 Hz),6.87(1H,s), 7.06(2H,d,J=8.79 Hz), 7.50(2H,d,J=9.04 Hz).

IR (KBr) cm⁻¹: 1656,1609,1513,1295,1248,1176,1026,833.

Example 166 Preparation of5,6-bis(4-methoxyphenyl)-2-isopropyl-2H-pyridazin-3-one

Similarly to Example 163, the title compound was obtained in a yield of68.1%.

Colorless prisms (ethyl acetate-diethyl ether).

Melting point: 128.3-129.1° C.

¹H-NMR (CDCl₃) δ: 1.00(3H,s), 1.02(3H,s), 2.35-2.40(1H,m), 3.79(3H,s),3.81(3H,s), 4.08(2H,d,J=7.57 Hz), 6.79(2H,d,J=8.79 Hz), 6.81(2H,d,J=8.79Hz), 6.89(1H,s), 7.05(2H,d,J=8.79 Hz), 7.12(2H,d,J=9.04 Hz).

IR (KBr) cm⁻¹: 2958,1660,1606,1515,1248,1177,1027,837.

Example 167 Preparation of2-allyl-5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one

Similarly to Example 163, the title compound was obtained in a yield of40.2%.

Pale yellow needles (ethyl acetate-n-hexane).

Melting point: 114.0-115.0° C.

¹H-NMR (CDCl₃) δ: 3.79(3H,s), 3.81(3H,s), 4.86(2H,d,J=5.86 Hz),5.28(1H,d,J=10.25 Hz), 5.33(1H,d,J=17.09 Hz),6.10(1H,tdd,J=5.86,10.25,17.09 Hz), 6.78(2H,d,J=8.79 Hz),6.81(2H,d,J=8.79 Hz), 6.90(1H,s), 7.04(2H,d,J=9.03 Hz), 7.12(2H,d,J=8.79Hz).

IR (KBr) cm⁻¹: 1662,1608,1511,1296,1250,1022,836.

Example 168 Preparation of5,6-bis(4-methoxyphenyl)-2-cyclo-propyl-2H-pyridazin-3-one

Similarly to Example 163, the title compound was obtained in a yield of2.3%.

Pale yellow oil.

Mass (m/e): 348 (M⁺).

¹H-NMR (CDCl₃) δ: 1.00-1.18(2H,m), 1.20-2.25(2H,m), 3.79(3H,s),3.81(3H,s), 4.20-4.30(1H,m), 6.77(2H,d,J=9.28 Hz), 6.81(2H,d,J=8.79 Hz),6.89(1H,s), 7.05(2H,d,J=9.03 Hz), 7.14(2H,d,J=9.03 Hz).

IR (KBr) cm⁻¹: 1733,1661,1652,1609,1515,1296,1250,1179, 1111,1026,834.

Example 169 Preparation of5,6-bis(4-methoxyphenyl)-2-cyclo-propylmethyl-2H-pyridazin-3-one

Similarly to Example 163, the title compound was obtained in a yield of89.6%.

Pale yellow crystalline powder (chloroform-diethyl ether-n-hexane).

Melting point: 128.8-129.3° C.

¹H-NMR (CDCl₃) δ: 0.46-0.62(4H,m), 1.38-1.54(1H,m), 3.80(3H,s),3.81(3H,s), 4.12(2H,d,J=7.08 Hz), 6.79(2H,d,J=9.04 Hz), 6.81(2H,d,J=8.79Hz), 6.90(1H,s), 7.06(2H,d,J=8.79 Hz), 7.10(2H,d,J=8.79 Hz).

IR (KBr) cm⁻¹: 1656,1609,1566,1514,1247,1183,1028,838.

Example 170 Preparation of5,6-bis(4-methoxyphenyl)-2-cyclo-propylmethyl-2H-pyridazine-3-thione

Lawessan's reagent (184 mg, 0.46 mmol) was added to a solution of5,6-bis(4-methoxyphenyl)-2-cyclo-propylmethyl-2H-pyridazin-3-one (165mg, 0.46 mmol) in toluene (6 ml), followed by stirring at 70° C. for 1hour under a nitrogen gas atmosphere. The solvent was distilled off, andthe resulting residue was separated and purified by chromatography on asilica gel column [silica gel: 18 g, n-hexane/ethyl acetate (4/1)].Crystallization was then effected from ethyl acetate-diethyl ether,whereby the title compound (127 mg, 72.9%) was obtained as yellowscales.

Melting point: 147.5-148.5° C.

¹H-NMR (CDCl₃) δ: 0.56-0.62(4H, m), 1.68-1.75(1H,m), 3.81(3H,s),3.82(3H,s), 4.64(2H,d,J=7.33 Hz), 6.81(2H,d,J=9.04 Hz), 6.82(2H,d,J=9.03Hz), 7.09(2H,d,J=8.79 Hz), 7.19(2H,d,J=9.03 Hz), 7.82(1H,s).

IR (KBr) cm⁻¹: 1609,1513,1416,1248,1186,1181,1122,1021, 834.

Example 171 Preparation of5,6-bis(4-methoxyphenyl)-2-cyclo-pentyl-2H-pyridazin-3-one

Similarly to Example 163, the title compound was obtained in a yield of65.4%.

Pale yellow prisms (chloroform-n-hexane).

Melting point: 141.2-142.2° C.

Mass (m/e): 376 (M⁺).

¹H-NMR (CDCl₃) δ: 1.60-1.80(2H,m), 1.80-2.20(6H,m), 3.80(3H,s),3.81(3H,s), 5.25(2H,quintet,J=6.60 Hz), 6.78(2H,d,J=8.79 Hz),6.82(2H,d,J=8.79 Hz), 6.86(1H,s), 7.06(2H,d,J=9.03 Hz), 7.14(2H,d,J=9.03Hz).

IR (KBr) cm⁻¹: 1661,1611,1512,1295,1255,1175,1020,833.

Example 172 Preparation of5,6-bis(4-methoxyphenyl)-2-cyclo-pentylmethyl-2H-pyridazin-3-one

Similarly to Example 163, the title compound was obtained in a yield of57.1%.

Colorless scales (ethyl acetate-diethyl ether).

Melting point: 130.3-131.4° C.

¹H-NMR (CDCl₃) δ: 1.37-1.79(8H,m), 2.56(1H,quintet,J=7.57 Hz),3.80(3H,s), 3.81(3H,s), 4.21(2H,d,J=7.82 Hz), 6.79(2H,d,J=8.79 Hz),6.81(2H,d,J=8.54 Hz), 6.89(1H,s), 7.05(2H,d,J=9.04 Hz), 7.13(2H,d,J=9.04Hz).

IR (KBr) cm⁻¹: 1664,1609,1513,1292,1250,1179,1023,831.

Test 1

Inhibitory Activity Against Interleukin-1β Production

HL-60 cells were cultured for 4 days until confluence on RPMI 1640medium with 10% fetal bovine serum (FBS) added thereto. The HL-60 cellswere centrifuged. The supernatant was discarded, and the cells were thensuspended at 1×10⁶ cells/ml on RPMI 1640 medium with 3% FBS, andlipopolysaccharide was added to give a final concentration of 10 μg/ml.The culture was inoculated at 1 ml/well to a 24-well plate. A testsample was added at 1 μl/well, followed by culturing for 3 days. Threedays later, the amount of interleukin-1β in each of the cultures wasmeasured by ELISA. Its IC₅₀ value was determined by a comparison inyield with a control to which no test sample was added. Results on somerepresentative compounds are shown in Table 1. TABLE 1 InhibitoryActivity against Interleukin-1β (IL-1β) Production Test compound IL-1βTest compound IL-1β (Example No.) IC₅₀ (μM) (Example No.) IC₅₀ (μM) 120.10 123 0.19 13 0.26 126 0.15 14 0.094 128 0.31 16 0.23 134 0.20 190.079 135 0.39 23 0.36 137 0.27 24 0.20 142 0.18 25 0.18 160 0.49 260.15 163 0.61 27 0.18 164 1.13 28 0.29 165 1.32 30 0.17 168 7.98 310.095 169 1.80 35 0.21 170 1.19 40 0.27 171 0.51 44 0.43 172 0.11 510.29 Comp. Comp'd 1 29 55 0.25 Comp. Comp'd 2 46 61 0.21 Comp. Comp'd3 >100 65 0.39 Comp. Comp'd 4 31.6 78 0.39 (Comp. Comp'd 1)

(Comp. Comp'd 2)

(Comp. Comp'd 3)

(Comp. Comp'd 4)

Test 2

Inhibitory Activity Against TNF-α Production

RAW 264.7 cells were cultured until confluence on DMEM culture with 10%fetal bovine serum (FBS), and were diluted to 1×10⁶ cells/ml with thesame medium and then inoculated at 100 μl/well to a 96-well plate. Tothe cells, a test sample which had been diluted with the same medium andlipopolysaccharide of 4 μg/ml was added at 50 μl/well, respectively.Subsequent to culturing for 20 hours, the cultures were collected.

Making use of cytotoxicity to L-929 cell strain, a TNF-α sensitive cellstrain, the amount of TNF-α in each of the cultures was measured as willbe described next. Described specifically, L-929 cells which had beencultured on MEM medium with 10% FBS added thereto were diluted to 2×10⁵cells/ml with the same medium, and were then inoculated at 100 μl/wellto a 96-well plate. Subsequent to overnight incubation, standard TNF-αsolutions, or 100-fold, 200-fold and 500-fold dilute solutions of theabove-described culture of RAW 264.7 cells were added at 50 μl/well, andactinomycin D (4 μg/ml) was also added at 50 μl/well, followed byfurther culturing for 20 hours. Twenty hours later, each well was washedwith PBS, viable cells were stained with crystal violet, and theinhibitory activity against TNF-α production was determined withreference to a standard curve of TNF-α. The results are shown in Table2.

Inhibitory Activity Against IL-6 Production

RAW 264.7 cells, which had been cultured until confluence on DMEMculture with 10% fetal bovine serum (FBS) added thereto, were diluted to1×10⁶ cells/ml with the same medium, and were then inoculated at 100μl/well to a 96-well plate. A test sample which had been diluted withthe same medium and lipopolysaccharide of 4 μg/ml in concentration wasadded at 50 μl/well, respectively. Subsequent to culturing for 20 hours,the cultures were collected.

The amount of IL-6 in each of the thus-obtained cultures of RAW 264.7cells was measured by ELISA, and the inhibitory activity against IL-6production was determined with reference to a standard curve of IL-6.The results are shown in Table-2. TABLE 2 Inhibitory Activity againstTNF-α and IL-6 Production Test compound TNF-α IL-6 (Example No.) IC₅₀(μM) IC₅₀ (μM) 163 1.2 0.40 Comparative Compound 1 10 65 ComparativeCompound 2 26 44

As is apparent from Tests 1 and 2 described above, the compoundsaccording to the present invention have been found to have extremelygood IL-1β inhibitory activity compared with Comparative Compounds 1 to4, which are compounds disclosed in EUR. J. MED. CHEM., 14, 53-60, 1979and are known to have anti-inflammatory and analgesic action.

Test 3

In accordance with the disclosure of Nature 283, 666-668, 1980,therapeutic effects for arthritis were evaluated by usingcollagen-induced arthritis models of mice. As a result, the compoundaccording to the present invention showed excellent arthritis treatmenteffects as shown in Table 3. TABLE 3 Percent¹⁾ inhibition Percent²⁾ Testcomp'd Dose to arthritis inhibition (Ex. No.) (mg/kg, P.O.) developmentto swelling 51 1 40 33.3 51 3 50 77.4¹⁾Determined depending on the existence or non-existence of swelling.²⁾Determined by quantitation of swelling.

Test 4

The compound of Example 51 was administered orally once a day to ratsand dogs for 2 weeks to determine its maximum no-effect level (theamount which does not show toxicity). As a result, no toxicity wasobserved at all at the dose levels of the compound shown in Table 4, sothat the compounds according to the present invention have been found tohave high safety. TABLE 4 Test compound Maximum no-effect Maximumno-effect (Example No.) level (rat) level (dog) 51 100 mg/kg 30 mg/kgCapability of Exploitation in Industry

The pyridazine derivatives (1) and their salts, which pertain to thepresent invention, have excellent inhibitory activity againstinterleukin-1β production, and are useful as medicines such aspreventives and therapeutics for immune system diseases, inflammatorydiseases and ischemic diseases.

1. A pyridazine derivative represented by the following formula (1):

wherein R¹ represents a substituted or unsubstituted aryl group, R²represents a phenyl group substituted at least at 4-position by a loweralkoxyl group, a lower alkylthio group, a lower alkylsulfinyl group or alower alkylsulfonyl group., and optionally has one or more substituentsat-the remaining positions, R³ represents a hydrogen atom, a loweralkoxyl group, a halogenated lower alkyl group, a lower cycloalkylgroup, a substituted or unsubstituted aryl group, a substituted orunsubstituted aryloxy group, a substituted or unsubstituted,nitrogen-containing heterocyclic ring residue, a substituted orunsubstituted aminocarbonyl group, or a lower alkylcarbonyl group, Arepresents a single bond or a linear or branched lower alkylene group orlower alkenylene group, X represents an oxygen atom or a sulfur atom,and the dashed line indicates that the carbon-carbon bond between the4-position and the 5-position is a single bond or a double bond, withthe proviso that A is a single bond when R³ is a halogenated lower alkylgroup and that the following combinations are excluded: R¹ and R² are4-methoxyphenyl groups, X is an oxygen atom, the carbon-carbon bond atthe 4-position and the 5-position is a double bond, A is a single bond,and R³ is a hydrogen atom or a 2-chloroethyl group; or a salt thereof.2. A pyridazine derivative or a salt thereof according to claim 1,wherein R¹ represents a substituted or unsubstituted phenyl or pyridylgroup.
 3. A pyridazine derivative or a salt thereof according to claim1, wherein R¹ represents a phenyl or pyridyl group which may besubstituted by 1 to 3 substituents selected from halogen atoms and loweralkoxy groups; R² represents a phenyl group, which may be substituted at4-position by a lower alkoxyl group, a lower alkylthio group, a loweralkylsulfinyl group or a lower alkylsulfonyl group, and at the otherpositions by 1 or 2 substituents selected from halogen atoms, loweralkoxyl groups, lower alkylthio groups, lower alkylsulfinyl groups andlower alkylsulfonyl groups; R³ represents a hydrogen atom, a loweralkoxyl group, a halogenated lower alkyl group, a lower cycloalkylgroup, a phenyl, pyridyl or phenyloxy group which may be substituted by1 to 3 substituents selected from halogen atoms, lower alkyl groups,lower alkoxyl groups, carboxyl group, lower alkoxycarbonyl groups, nitrogroup, amino group, lower alkylamino groups and lower alkylthio groups,a substituted or unsubstituted piperidino, piperidyl, piperazino ormorpholino group, a substituted or unsubstituted aminocarbonyl group, ora lower alkylcarbonyl group; and A represents a linear or branched loweralkylene group having 1 to 6 carbon atoms or a linear or branchedalkenylene group having 2 to 9 carbon atoms.
 4. A pyridazine derivativeor a salt thereof according to claim 1, which is a compound representedby the following formula (1A):

wherein R⁴ represents a linear or branched lower alkyl or loweralkenylene group, a lower cycloalkyl group or a lower cycloalkylmethylgroup, and X represents an oxygen atom or a sulfur atom; or a saltthereof.
 5. A pyridazine derivative or a salt thereof according to claim1, which is 5,6-bis(4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-isopropyl-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one,2-allyl-5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one,5,6-bis(4-methoxy-phenyl)-2-cyclopropyl-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazine-3-thione,5,6-bis(4-methoxyphenyl)-2-cyclopentyl-2H-pyridazin-3-one,5,6-bis(4-methoxy-phenyl)-2-cyclopentylmethyl-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-(4-chlorocinnamyl)-2H-pyridazin-3-one,5-(4-chlorophenyl)-6-(4-methylthiophenyl)-2-benzyl-2H-pyridazin-3-one,5,6-bis(4-methoxyphenyl)-2-benzyl-2H-pyridazine-3-thione, or5,6-bis(3-fluoro-4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one; or a saltthereof.
 6. A medicine comprising, as an effective ingredient, apyridazine derivative or a salt thereof according to any one of claims1-5.
 7. A medicine according to claim 6, which is an interleukin-1βproduction inhibitor.
 8. A medicine according to claim 6, which is apreventive or therapeutic for a disease caused by stimulation ofinterleukin-1β production.
 9. A medicine according to claim 6, which isa preventive or therapeutic for an immune system disease, aninflammatory disease, an ischemic disease, osteoporosis or ichorrhemia.10. A medicine according to claim 6, which is a preventive ortherapeutic for rheumatism, arthritis or inflammatory colitis.
 11. Aninterleukin-1β production inhibitor comprising, as an effectiveingredient, a pyridazine derivative or a salt thereof according to anyone of claims 1-5.
 12. A pharmaceutical composition comprising apyridazine derivative or a salt thereof according to any one of claims1-5 and a pharmaceutically acceptable carrier.
 13. Use of a pyridazinederivative or a salt thereof according to any one of claims 1-5 as amedicine.
 14. A method for the treatment of a disease caused bystimulation of interleukin-1β production, which comprises administeringa pyridazine derivative or a salt thereof according to any one of claims1-5.